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  • 1.
    Abdelrahim, Nada A.
    et al.
    Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, Nile University, Khartoum, Sudan.
    Mohamed, Nahla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Fadl-Elmula, Imad M.
    Department of Pathology and Clinical Genetics, Faculty of Medicine, Al-Neelain University, Khartoum, Sudan; Assafa Academy, Kartoum, Sudan.
    Human herpes virus type-6 is associated with central nervous system infections in children in Sudan2022In: African Journal of Laboratory Medicine, ISSN 2225-2002, E-ISSN 2225-2010, Vol. 11, no 1, article id a1718Article in journal (Refereed)
    Abstract [en]

    Background: Human herpes virus type-6 (HHV-6) is increasingly recognised as a febrile agent in children. However, less is known in sub-Saharan African countries, including Sudan.

    Objective: We investigated the involvement of HHV-6 in paediatric central nervous system (CNS) infections in Khartoum, Sudan.

    Methods: Febrile patients aged up to 15 years with suspected CNS infections at Omdurman Hospital for Children from 01 December 2009 to 01 August 2010 were included. Viral DNA was extracted from leftover cerebrospinal fluid (CSF) specimens and quantitatively amplified by real-time polymerase chain reaction (PCR) at Umeå University in Sweden.

    Results: Of 503 CSF specimens, 13 (2.6%) were positive for HHV-6 (33.0% [13/40 of cases with proven infectious meningitis]). The median thermal cycle threshold for all HHV-6-positive specimens was 38 (range: 31.9-40.8). The median number of virus copies was 281.3/PCR run (1 × 105 copies/mL CSF; range: 30-44 × 103 copies/PCR run [12 × 103 - 18 × 106 copies/mL CSF]). All positive patients presented with fever and vomiting; 86.0% had seizures. The male-to-female ratio was 1:1; 50.0% were toddlers, 42.0% infants and 8.0% teenagers. Most (83.0%) were admitted in the dry season and 17.0% in the rainy season. Cerebrospinal fluid leukocytosis was seen in 33.0%, CSF glucose levels were normal in 86.0% and low in 14.0%, and CSF protein levels were low in 14.0% and high in 43.0%.

    Conclusion: Among children in Sudan with CNS infections, HHV-6 is common. Studies on the existence and spread of HHV-6 chromosomal integration in this population are needed.

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  • 2.
    Ahlm, Clas
    et al.
    Infektionskliniken, Norrlands universitetssjukhus, Umeå, Sweden.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Missfall orsakades av det myggburna Rift Valley-feberviruset2016In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 113, no 42, article id EAUZArticle in journal (Other academic)
  • 3. Alberione, Maria Pia
    et al.
    Moeller, Rebecca
    Kirui, Jared
    Ginkel, Corinne
    Doepke, Mandy
    Stroeh, Luisa J.
    Machtens, Jan-Philipp
    Pietschmann, Thomas
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Single-nucleotide variants in human CD81 influence hepatitis C virus infection of hepatoma cells2020In: Medical Microbiology and Immmunology, ISSN 0300-8584, E-ISSN 1432-1831, Vol. 209, no 4, p. 499-514Article in journal (Refereed)
    Abstract [en]

    An estimated number of 71 million people are living with chronic hepatitis C virus (HCV) infection worldwide and 400,000 annual deaths are related to the infection. HCV entry into the hepatocytes is complex and involves several host factors. The tetraspanin human CD81 (hCD81) is one of the four essential entry factors and is composed of one large extracellular loop, one small extracellular loop, four transmembrane domains, one intracellular loop and two intracellular tails. The large extracellular loop interacts with the E2 glycoprotein of HCV. Regions outside the large extracellular loop (backbone) of hCD81 have a critical role in post-binding entry steps and determine susceptibility of hepatocytes to HCV. Here, we investigated the effect of five non-synonymous single-nucleotide variants in the backbone of hCD81 on HCV susceptibility. We generated cell lines that stably express the hCD81 variants and infected the cells using HCV pseudoparticles and cell culture-derived HCV. Our results show that all the tested hCD81 variants support HCV pseudoparticle entry with similar efficiency as wild-type hCD81. In contrast, variants A54V, V211M and M220I are less supportive to cell culture-derived HCV infection. This altered susceptibility is HCV genotype dependent and specifically affected the cell entry step. Our findings identify three hCD81 genetic variants that are impaired in their function as HCV host factors for specific viral genotypes. This study provides additional evidence that genetic host variation contributes to inter-individual differences in HCV infection and outcome.

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  • 4.
    Alfaifi, Sarah
    et al.
    Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
    Suliman, Rania
    Department of Clinical Laboratory Sciences, Prince Sultan Military College of Health Sciences, Dhahran, Saudi Arabia.
    Idriss, Mona Timan
    Department of Pharmaceutics, Faculty of Pharmacy, Imperial University College, Khartoum, Sudan; Department of Medical Sciences and Preparation Year, Northern College of Nursing, Arar, Saudi Arabia.
    Aloufi, Abeer S.
    Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
    Alolayan, Ebtesam
    Department of Zoology, King Saud University, Riyadh, Saudi Arabia.
    Awadalla, Maaweya
    Research Center, King Fahad Medical City, Riyadh, Saudi Arabia.
    Aodah, Alhassan
    Life Science & Environment Research Institute, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
    Asab, Omar Abu
    Life Science & Environment Research Institute, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
    Al-Qahtani, Jarallah
    Department of Histopathology, King Fahad Military Medical Complex, Dhahran, Saudi Arabia.
    Mohmmed, Nahla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Alosaimi, Bandar
    Research Center, King Fahad Medical City, Riyadh, Saudi Arabia.
    In vivo Evaluation of the Antiviral Effects of Arabian Coffee (Coffea arabica) and Green Tea (Camellia sinensis) Extracts on Influenza A Virus2023In: International Journal of Biomedicine, ISSN 2158-0510, Vol. 13, no 3, p. 154-161Article in journal (Refereed)
    Abstract [en]

    This in vivo study was conducted to evaluate the antiviral activity of Arabian coffee (Coffea arabica) and green tea (Camellia sinensis) extracts against the influenza virus. High-performance liquid chromatography (HPLC) was used to determine the active components in each extract, and eighty experimental mice were treated. Electrophoresis was performed to detect protein expression, and reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze gene expression and quantify viral RNA. Lung tissue histopathology was processed to observe pathological signs. Oral administration of all extracts reduced the viral quantification in mice lungs by 61.6% in the early phase of infection, measured by PCR. From the extracts tested, unroasted green Arabica coffee (AC) extract in protective groups showed remarkable body weight stability of 16.76 g, a survival rate of 100%, and healthier lung tissue, compared to other groups. The antiviral effects of the tested AC and GT (green tea) revealed that AC extracts induced veridical effects, increased body weight, and improved survival rate. Those natural extracts may interfere with viral replication and reduce virus infection. The observed anti-influenza activity demonstrated by reduced symptoms and increased survival rate in animal models suggests that AC extracts might be used as a promising prophylactic agent against influenza viral infections. The active compound in the unroasted green AC extract requires further in vitro analysis as to which viral proteins are targeted by the natural extract and which molecular mechanism this antiviral inhibition is interfering with.

  • 5. Andersen, Petter I.
    et al.
    Krpina, Klara
    Ianevski, Aleksandr
    Shtaida, Nastassia
    Jo, Eunji
    Yang, Jaewon
    Koit, Sandra
    Tenson, Tanel
    Hukkanen, Veijo
    Anthonsen, Marit W.
    Bjoras, Magnar
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Windisch, Marc P.
    Zusinaite, Eva
    Kainov, Denis E.
    Novel Antiviral Activities of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine2019In: Viruses, E-ISSN 1999-4915, Vol. 11, no 10, article id 964Article in journal (Refereed)
    Abstract [en]

    Viruses are the major causes of acute and chronic infectious diseases in the world. According to the World Health Organization, there is an urgent need for better control of viral diseases. Repurposing existing antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we identified novel activities of obatoclax and emetine against herpes simplex virus type 2 (HSV-2), echovirus 1 (EV1), human metapneumovirus (HMPV) and Rift Valley fever virus (RVFV) in cell cultures. Moreover, we demonstrated novel activities of emetine against influenza A virus (FLUAV), niclosamide against HSV-2, brequinar against human immunodeficiency virus 1 (HIV-1), and homoharringtonine against EV1. Our findings may expand the spectrum of indications of these safe-in-man agents and reinforce the arsenal of available antiviral therapeutics pending the results of further in vitro and in vivo tests.

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  • 6.
    Arnberg, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
    Special issue "adenovirus pathogenesis"2021In: Viruses, E-ISSN 1999-4915, Vol. 13, no 6, article id 1112Article in journal (Other academic)
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  • 7.
    Ballmann, Mónika Z.
    et al.
    Batavia Biosciences B.V., Leiden, Netherlands.
    Raus, Svjetlana
    Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, United Kingdom.
    Engelhart, Ruben
    Batavia Biosciences B.V., Leiden, Netherlands; Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, United Kingdom.
    Kaján, Gyõzõ L.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Beqqali, Abdelaziz
    Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, United Kingdom.
    Hadoke, Patrick W.F.
    Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, United Kingdom.
    van der Zalm, Chantal
    Batavia Biosciences B.V., Leiden, Netherlands.
    Papp, Tibor
    Janssen Vaccines and Prevention B.V., Leiden, Netherlands.
    Lijo, John
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Khan, Selina
    Janssen Vaccines and Prevention B.V., Leiden, Netherlands.
    Boedhoe, Satish
    Janssen Vaccines and Prevention B.V., Leiden, Netherlands.
    Danskog, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Custers, Jerome
    Janssen Vaccines and Prevention B.V., Leiden, Netherlands.
    Bakker, Wilfried A.M.
    Batavia Biosciences B.V., Leiden, Netherlands.
    van der Schaar, Hilde M.
    Batavia Biosciences B.V., Leiden, Netherlands.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Lemckert, Angelique A.C.
    Batavia Biosciences B.V., Leiden, Netherlands.
    Havenga, Menzo
    Batavia Biosciences B.V., Leiden, Netherlands.
    Baker, Andrew H.
    Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, United Kingdom.
    Human AdV-20-42-42, a promising novel adenoviral vector for gene therapy and vaccine product development2021In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 95, no 22, article id e00387-21Article in journal (Refereed)
    Abstract [en]

    Preexisting immune responses toward adenoviral vectors limit the use of a vector based on particular serotypes and its clinical applicability for gene therapy and/or vaccination. Therefore, there is a significant interest in vectorizing novel adenoviral types that have low seroprevalence in the human population. Here, we describe the discovery and vectorization of a chimeric human adenovirus, which we call HAdV-20-42-42. Full-genome sequencing revealed that this virus is closely related to human serotype 42, except for the penton base, which is derived from serotype 20. The HAdV-20-42-42 vector could be propagated stably to high titers on existing E1-complementing packaging cell lines. Receptor-binding studies revealed that the vector utilized both CAR and CD46 as receptors for cell entry. Furthermore, the HAdV-20-42-42 vector was potent in transducing human and murine cardiovascular cells and tissues, irrespective of the presence of blood coagulation factor X. In vivo characterizations demonstrate that when delivered intravenously (i.v.) in mice, HAdV-20-42-42 mainly targeted the lungs, liver, and spleen and triggered robust inflammatory immune responses. Finally, we demonstrate that potent T-cell responses against vector-delivered antigens could be induced upon intramuscular vaccination in mice. In summary, from the data obtained we conclude that HAdV-20-42-42 provides a valuable addition to the portfolio of adenoviral vectors available to develop efficacious products in the fields of gene therapy and vaccination.

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  • 8. Bashir, Rania Salah Eldien
    et al.
    Hassan, Osama Ahmed
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    A One Health perspective to identify environmental factors that affect Rift Valley fever transmission in Gezira state, Central Sudan2019In: Tropical Medicine and Health, ISSN 1348-8945, E-ISSN 1349-4147, Vol. 47, no 1, article id 54Article in journal (Refereed)
    Abstract [en]

    Background: Rift Valley fever (RVF) is a zoonotic viral vector-borne disease that affects both animals and humans and leads to severe economic consequences. RVF outbreaks are triggered by a favorable environment and flooding, which enable mosquitoes to proliferate and spread the virus further. RVF is endemic to Africa and has spread to Saudi Arabia and Yemen. There is great concern that RVF may spread to previously unaffected geographic regions due to climate change. We aimed to better understand the spatiotemporal pattern of the 2007 RVF outbreak at the human-animal-environment interface and to determine environmental factors that may have effects on RVF occurrence in Gezira state, Sudan.

    Materials and methods: We compiled epidemiological, environmental, and spatiotemporal data across time and space using remote sensing and a geographical information system (GIS). The epidemiological data included 430 RVF human cases as well as human and animal population demographic data for each locality. The cases were collected from 41 locations in Gezira state. The environmental data represent classified land cover during 2007, the year of the RVF outbreak, and the average of the Normalized Difference Vegetation Index (NDVI) for 6 months of 2007 is compared with those of 2010 and 2014, when there was no RVF outbreak. To determine the effect of the environmental factors such as NDVI, soil type, and RVF case's location on the Blue Nile riverbank on RVF incidence in Gezira state, a multilevel logistic regression model was carried out.

    Results: We found that the outbreak in Gezira state occurred as a result of interaction among animals, humans, and the environment. The multilevel logistic regression model (F = 43,858, df = 3, p = 0.000) explained 23% of the variance in RVF incidence due to the explanatory variables. Notably, soil type (beta = 0.613, t = 11.284, p = 0.000) and NDVI (beta = - 0.165, t = - 3.254, p = 0.001) were the explanatory environmental factors that had significant effects on RVF incidence in 2007 in Gezira state, Sudan.

    Conclusions: Precise remote sensing and the GIS technique, which rely on environmental indices such as NDVI and soil type that are satellite-derived, can contribute to establishing an early warning system for RVF in Sudan. Future preparedness and strengthening the capacity of regional laboratories are necessary for early notification of outbreaks in animals and humans.

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  • 9.
    Bouw, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Utsöndring av herpesvirus i saliv2020Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 10.
    Carriquí-Madroñal, Belén
    et al.
    Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hanover, Hanover, Germany; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hanover, Germany.
    Lasswitz, Lisa
    Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hanover, Hanover, Germany; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hanover, Germany.
    von Hahn, Thomas
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Interventional Endoscopy, Asklepios Hospital Barmbek, Semmelweis University, Campus Hamburg, Hamburg, Germany.
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hanover, Hanover, Germany; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, the Medical School Hannover/the Helmholtz Centre for Infection Research, Hanover, Germany.
    Genetic and pharmacological perturbation of hepatitis-C virus entry2023In: Current Opinion in Virology, ISSN 1879-6257, E-ISSN 1879-6265, Vol. 62, article id 101362Article, review/survey (Refereed)
    Abstract [en]

    Hepatitis-C virus (HCV) chronically infects 58 million individuals worldwide with variable disease outcome. While a subfraction of individuals exposed to the virus clear the infection, the majority develop chronic infection if untreated. Another subfraction of chronically ill proceeds to severe liver disease. The underlying causes of this interindividual variability include genetic polymorphisms in interferon genes. Here, we review available data on the influence of genetic or pharmacological perturbation of HCV host dependency factors on the clinically observed interindividual differences in disease outcome. We focus on host factors mediating virus entry into human liver cells. We assess available data on genetic variants of the major entry factors scavenger receptor class-B type I, CD81, claudin-1, and occludin as well as pharmacological perturbation of these entry factors. We review cell culture experimental and clinical cohort study data and conclude that entry factor perturbation may contribute to disease outcome of hepatitis C.

  • 11.
    Carriquí-Madroñal, Belén
    et al.
    Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hanover, Germany.
    Sheldon, Julie
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hanover, Germany.
    Duven, Mara
    Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hanover, Germany.
    Stegmann, Cora
    Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hanover, Germany.
    Cirksena, Karsten
    Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hanover, Germany.
    Wyler, Emanuel
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany.
    Zapatero-Belinchón, Francisco J.
    Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hanover, Germany; Gladstone Institutes, CA, San Francisco, United States.
    Vondran, Florian W. R.
    Department of General, Visceral and Transplant Surgery, Regenerative Medicine and Experimental Surgery, Hannover Medical School, Hannover, Germany; German Center for Infection Research Partner Site Hannover-Braunschweig Hannover, Germany.
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hanover, Germany; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hanover, Germany.
    The matrix metalloproteinase ADAM10 supports hepatitis C virus entry and cell-to-cell spread via its sheddase activity2023In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 19, no 11, article id e1011759Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV) exploits the four entry factors CD81, scavenger receptor class B type I (SR-BI, also known as SCARB1), occludin, and claudin-1 as well as the co-factor epidermal growth factor receptor (EGFR) to infect human hepatocytes. Here, we report that the disintegrin and matrix metalloproteinase 10 (ADAM10) associates with CD81, SR-BI, and EGFR and acts as HCV host factor. Pharmacological inhibition, siRNA-mediated silencing and genetic ablation of ADAM10 reduced HCV infection. ADAM10 was dispensable for HCV replication but supported HCV entry and cell-to-cell spread. Substrates of the ADAM10 sheddase including epidermal growth factor (EGF) and E-cadherin, which activate EGFR family members, rescued HCV infection of ADAM10 knockout cells. ADAM10 did not influence infection with other enveloped RNA viruses such as alphaviruses and a common cold coronavirus. Collectively, our study reveals a critical role for the sheddase ADAM10 as a HCV host factor, contributing to EGFR family member transactivation and as a consequence to HCV uptake.

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  • 12.
    Chandra, Naresh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University.
    The glycobiology of human adenovirus infections: implications for tropism and treatment2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human adenoviruses (HAdVs) are common human pathogens, causing gastrointestinal, ocular, and respiratory infections on a regular basis. Epidemic keratoconjunctivitis (EKC) is a severe ocular infection for which no approved antivirals are available. HAdV-D37 is one of the causative agents of EKC and uses sialic acid (SA)-containing glycans as cellular receptors. HAdV-D37 interacts with SA via the knob domain of the trimeric virus fiber protein, containing three SA-binding sites. HAdV-D37 also bind to glycosaminoglycans (GAGs), but the outcome of this interaction remains unknown. Here, using biochemical and cell-based assays, the impact of GAGs on HAdV-D37 infection (paper I) was investigated. We found that HAdV-D37 interacts with both soluble and cell-surface sulfated GAGs via the knob domain of the viral fiber protein. Remarkably, removal of heparan sulfate (HS; a type of GAG) from human corneal epithelial (HCE) cells by heparinase III enhanced HAdV-D37 infection. We propose that sulfated GAGs in bodily secretions and on plasma membranes function as decoy receptors that prevent the virus from binding to SA-containing receptors and inhibit subsequent virus infection. We also found abundant HS in the basement membrane of the human corneal epithelium. We suggest that this layer of HS functions as a barrier to sub-epithelial infection of HAdV-D37. Based on this finding, we hypothesized that GAG-mimetics may act as artificial decoy receptors and inhibit HAdV-D37 infection. Here, the antiviral effect of suramin (a known GAG-mimetic) and its analogs against HAdV-D37 (paper II) was evaluated. Interestingly, all compounds displayed antiviral effects by inhibiting the binding of HAdV-D37 to HCE cells. The antiviral effect of suramin was HAdV species-specific. We report for the first time that virus binding to cell-surface decoy receptor constitutes a potential target for antiviral drug development.

    HAdVs are the major cause of infectious conjunctivitis, constituting up to 75% of all conjunctivitis cases worldwide. Species B HAdV type 3 (HAdV-B3) causes pharyngoconjunctival fever (PCF), whereas HAdV-D8, -D37, and -D64 cause EKC. Recently, HAdV-D53, -D54, and -D56 have emerged as new EKC-causing agents. HAdV-E4 causes both PCF and EKC. SA-containing glycans have been established as cellular receptors for HAdV-D37. By means of cell-based assays, we investigated if ocular HAdVs other than HAdV-D37 also use SA-containing glycans as receptors on HCE cells (paper III). It was found that SA-containing glycans function as cellular receptors for five (HAdV-D8, -D37, -D53, -D54, and -D64) out of six EKC-causing species D HAdVs. We showed that these viruses interact with SAs via the knob domain of the viral fiber protein. HAdV-E4 and -D56 infection of cells was independent of SAs. Surprisingly, HCE cells were completely refractory to HAdV-B3 infection. A trivalent sialic acid (TSA) derivative ME0462 (compound 17a in paper II), designed to bind to SA-binding sites on HAdV-D37 fiber knob, also showed potent antiviral activity against several EKC-causing HAdVs. This suggests that ME0462 can be used as a broad-spectrum antiviral against known and emerging EKC-causing HAdVs. Surface plasmon resonance (SPR) analysis confirmed a direct interaction between ME0462 and fiber knobs of EKC-causing HAdVs.

    Recently, a TSA derivative (ME0322; designed to bind to SA-binding sites on HAdV-D37 fiber knob) was shown potent antiviral against HAdV-D37 in vitro. To improve the antiviral potency of this compound, six new TSA derivatives were synthesized and their inhibitory effects were evaluated against HAdV-D37 (paper IV). Interestingly, the best compound 17a was found approximately three orders of magnitude more potent (IC50 (binding) = 1.4 nM, IC50 (infection) = 2.9 nM) than ME0322 (IC50 in µM range). SPR data showed that HAdV-D37 fiber knob binds to TSA compounds with high affinities. Structural data revealed the trivalent binding mode of all newly synthesized TSA compounds to HAdV-D37 fiber knob. Ophthalmic toxicity of compound 17a (best compound) was also investigated in rabbits without any sign of toxicity.

    HAdV-D36 is a member of species D HAdV and has the ability to infect a broad range of animals, which is unusual for HAdVs. Another remarkable feature of HAdV-D36 is that this virus induces obesity in experimental animals. Several epidemiological studies highlighted a link between HAdV-D36 and human obesity. There is no information about the cellular receptor usage by HAdV-D36. Using structural biology and cell-based approaches, we investigated the cellular receptor(s) for HAdV-D36 (paper V).  We show that HAdV-D36 attaches to host cells (via the fiber knob) using the coxsackie and adenovirus receptor (CAR), SA-containing glycans, and one or more unknown proteins or glycoproteins. Using glycan microarray, we found that HAdV-D36 displays binding preference to a rare SA-variant: 4-O,5-N-diacetylneuraminic acid (Neu4,5Ac2), over the more common SA (in humans) i.e. 5-N-acetylneuraminic acid (Neu5Ac). Structural analysis of HAdV-D36 fiber knob:Neu4,5Ac2 complex explained this preference. To date, Neu4,5Achas not been detected in humans, although it is synthesized by many domestic and livestock animals. Our results indicate that HAdV-D36 has evolved to utilize a specialized set of cellular receptors that coincide with a unique host range and pathogenicity profile.

    These studies provide insights into multiple roles of glycans in HAdV infection cycle and highlight the therapeutic potential of glycans/glycan-mimetics in HAdV-D37 infection.

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  • 13.
    Chandra, Naresh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Decoy Receptor Interactions as Novel Drug Targets against EKC-Causing Human Adenovirus2019In: Viruses, E-ISSN 1999-4915, Vol. 11, no 3, article id E242Article in journal (Refereed)
    Abstract [en]

    Epidemic keratoconjunctivitis (EKC) is a severe ocular disease and can lead to visual impairment. Human adenovirus type-37 (HAdV-D37) is one of the major causative agents of EKC and uses sialic acid (SA)-containing glycans as cellular receptors. Currently, there are no approved antivirals available for the treatment of EKC. Recently, we have reported that sulfated glycosaminoglycans (GAGs) bind to HAdV-D37 via the fiber knob (FK) domain of the viral fiber protein and function as decoy receptors. Based on this finding, we speculated that GAG-mimetics may act as artificial decoy receptors and inhibit HAdV-D37 infection. Repurposing of approved drugs to identify new antivirals has drawn great attention in recent years. Here, we report the antiviral effect of suramin, a WHO-approved drug and a widely known GAG-mimetic, against HAdV-D37. Commercially available suramin analogs also show antiviral effects against HAdV-D37. We demonstrate that suramin exerts its antiviral activity by inhibiting the attachment of HAdV-D37 to cells. We also reveal that the antiviral effect of suramin is HAdV species-specific. Collectively, in this proof of concept study, we demonstrate for the first time that virus binding to a decoy receptor constitutes a novel and an unexplored target for antiviral drug development.

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  • 14.
    Chandra, Naresh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Imhof, Sophie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Caraballo, Rémi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Sialic Acid-Containing Glycans as Cellular Receptors for Ocular Human Adenoviruses: Implications for Tropism and Treatment2019In: Viruses, E-ISSN 1999-4915, Vol. 11, no 5, article id 395Article in journal (Refereed)
    Abstract [en]

    Human adenoviruses (HAdV) are the most common cause of ocular infections. Species B human adenovirus type 3 (HAdV-B3) causes pharyngoconjunctival fever (PCF), whereas HAdV-D8, -D37, and -D64 cause epidemic keratoconjunctivitis (EKC). Recently, HAdV-D53, -D54, and -D56 emerged as new EKC-causing agents. HAdV-E4 is associated with both PCF and EKC. We have previously demonstrated that HAdV-D37 uses sialic acid (SA)-containing glycans as cellular receptors on human corneal epithelial (HCE) cells, and the virus interaction with SA is mediated by the knob domain of the viral fiber protein. Here, by means of cell-based assays and using neuraminidase (a SA-cleaving enzyme), we investigated whether ocular HAdVs other than HAdV-D37 also use SA-containing glycans as receptors on HCE cells. We found that HAdV-E4 and -D56 infect HCE cells independent of SAs, whereas HAdV-D53 and -D64 use SAs as cellular receptors. HAdV-D8 and -D54 fiber knobs also bound to cell-surface SAs. Surprisingly, HCE cells were found resistant to HAdV-B3 infection. We also demonstrated that the SA-based molecule i.e., ME0462, designed to bind to SA-binding sites on the HAdV-D37 fiber knob, efficiently prevents binding and infection of several EKC-causing HAdVs. Surface plasmon resonance analysis confirmed a direct interaction between ME0462 and fiber knobs. Altogether, we demonstrate that SA-containing glycans serve as receptors for multiple EKC-causing HAdVs, and, that SA-based compound function as a broad-spectrum antiviral against known and emerging EKC-causing HAdVs.

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  • 15.
    Chandra, Naresh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Liu, Yan
    Liu, Jing-Xia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Wu, Nian
    Silva, Lisete M
    Lindström, Mona
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Chai, Wengang
    Domellöf, Fatima Pedrosa
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Feizi, Ten
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Sulfated Glycosaminoglycans as Viral Decoy Receptors for Human Adenovirus Type 372019In: Viruses, E-ISSN 1999-4915, Vol. 11, no 3, article id E247Article in journal (Refereed)
    Abstract [en]

    Glycans on plasma membranes and in secretions play important roles in infection by many viruses. Species D human adenovirus type 37 (HAdV-D37) is a major cause of epidemic keratoconjunctivitis (EKC) and infects target cells by interacting with sialic acid (SA)-containing glycans via the fiber knob domain of the viral fiber protein. HAdV-D37 also interacts with sulfated glycosaminoglycans (GAGs), but the outcome of this interaction remains unknown. Here, we investigated the molecular requirements of HAdV-D37 fiber knob:GAG interactions using a GAG microarray and demonstrated that fiber knob interacts with a broad range of sulfated GAGs. These interactions were corroborated in cell-based assays and by surface plasmon resonance analysis. Removal of heparan sulfate (HS) and sulfate groups from human corneal epithelial (HCE) cells by heparinase III and sodium chlorate treatments, respectively, reduced HAdV-D37 binding to cells. Remarkably, removal of HS by heparinase III enhanced the virus infection. Our results suggest that interaction of HAdV-D37 with sulfated GAGs in secretions and on plasma membranes prevents/delays the virus binding to SA-containing receptors and inhibits subsequent infection. We also found abundant HS in the basement membrane of the human corneal epithelium, which may act as a barrier to sub-epithelial infection. Collectively, our findings provide novel insights into the role of GAGs as viral decoy receptors and highlight the therapeutic potential of GAGs and/or GAG-mimetics in HAdV-D37 infection.

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  • 16. Ecke, Frauke
    et al.
    Mahani, Seyed Alireza Nematollahi
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Hörnfeldt, Birger
    Khalil, Hussein
    Wildfire-induced short-term changes in a small mammal community increase prevalence of a zoonotic pathogen?2019In: Ecology and Evolution, E-ISSN 2045-7758, Vol. 9, no 22, p. 12459-12470Article in journal (Refereed)
    Abstract [en]

    Natural disturbances like droughts and fires are important determinants of wildlife community structure and are suggested to have important implications for prevalence of wildlife-borne pathogens. After a major wildfire affecting >1,600 ha of boreal forest in Sweden in 2006, we took the rare opportunity to study the short-term response (2007-2010 and 2015) of small mammal community structure, population dynamics, and prevalence of the Puumala orthohantavirus (PUUV) hosted by bank voles (Myodes glareolus). We performed snap-trapping in permanent trapping plots in clear-cuts (n = 3), unburnt reference forests (n = 7), and the fire area (n = 7) and surveyed vegetation and habitat structure. Small mammal species richness was low in all habitats (at maximum three species per trapping session), and the bank vole was the only small mammal species encountered in the fire area after the first postfire year. In autumns of years of peak rodent densities, the trapping index of bank voles was lowest in the fire area, and in two of three peak-density years, it was highest in clear-cuts. Age structure of bank voles varied among forest types with dominance of overwintered breeders in the fire area in the first postfire spring. PUUV infection probability in bank voles was positively related to vole age. Infection probability was highest in the fire area due to low habitat complexity in burnt forests, which possibly increased encounter rate among bank voles. Our results suggest that forest fires induce cascading effects, including fast recovery/recolonization of fire areas by generalists like bank voles, impoverished species richness of small mammals, and altered prevalence of a rodent-borne zoonotic pathogen. Our pilot study suggests high human infection risk upon encountering a bank vole in the fire area, however, with even higher overall risk in unburnt forests due to their higher vole numbers.

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  • 17.
    Elgh, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Stenberg, Göran
    Wennstedt, Ola
    Pehr Stenberg och hans levernesbeskrivning: en introduktion2020In: Historisk Tidskrift för Finland, ISSN 0046-7596, E-ISSN 2343-2888, Vol. 105, no 2, p. 117-125Article in journal (Other academic)
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  • 18.
    Fagerholm, Freja
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Hantavirusinfektion hos gråsiding och rödsork i Stora sjöfallet, norra Sverige2023Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 19.
    Gerold, Gisa
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. TWINCORE, Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany.
    Moeller, Rebecca
    Pietschmann, Thomas
    Hepatitis C Virus Entry: Protein Interactions and Fusion Determinants Governing Productive Hepatocyte Invasion2020In: Cold Spring Harbor Perspectives in Medicine, E-ISSN 2157-1422, Vol. 10, no 2, article id a036830Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV) entry is among the best-studied uptake processes for human pathogenic viruses. Uptake follows a spatially and temporally tightly controlled program. Numerous host factors including proteins, lipids, and glycans promote productive uptake of HCV particles into human liver cells. The virus initially attaches to surface proteoglycans, lipid receptors such as the scavenger receptor BI (SR-BI), and to the tetraspanin CD81. After lateral translocation of virions to tight junctions, claudin-1 (CLDN1) and occludin (OCLN) are essential for entry. Clathrin-mediated endocytosis engulfs HCV particles, which fuse with endosoma I membranes after pH drop. Uncoating of the viral RNA genome in the cytoplasm completes the entry process. Here we systematically review and classify HCV entry factors by their mechanistic role, relevance, and level of evidence. Finally, we report on more recent knowledge on determinants of membrane fusion and close with an outlook on future implications of HCV entry research.

  • 20.
    Gokumakulapalle, Madhuri
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Wang, Li
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Susceptibility of Dog, Hamster, and Mouse Cells to the Replication-Competent Adenovirus 11p E1/E3 Green Fluorescence Protein Vector Has Implications for the Selection of Animal Vaccine Models2021In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 12, article id 698999Article in journal (Refereed)
    Abstract [en]

    Human adenovirus (Ad)-vectored vaccines require viruses that can internalize into host cells and express the vaccine antigen. Evaluation of the expressed antigen in animal cells is a critical step in preclinical trials of viral vaccines. Due to the species specificity of Ads, it is difficult to find a suitable animal model. Thus, in this study, we compared the efficacy of Ad 11 prototype (Ad11p)-mediated green fluorescence protein (GFP) expression in cell lines of dog (MDCK), hamster (CHO), and mouse (McCoy and C127). Although these cell lines did not express the known primary cellular receptors for Ad11p virus infection (i.e., CD46), Ad11pE1GFP could infect and express GFP with various efficacies. For instance, it manifested relatively higher GFP expression in MDCK than in CHO, McCoy, and C127. However, infection leading to efficient viral release was not observed in any of the studied cell lines. The apparent differences were attributed to particularities of mouse and hamster cell lines, which might have led to the repression of viral DNA synthesis and to the low level of GFP expression mediated by Ad11pe3GFP. Moreover, our results revealed that undetectable hexon protein hampered the assembly of virus particles in CHO and MDCK cells. Ad11p differed from Ad5 in the ability for viral DNA synthesis when infecting CHO cells. Although a defective Ad has been successfully developed for SARS-CoV-2 vaccines in clinical applications, it has been difficult to generate one that can be used as an oral SARS-CoV-2 vaccine. Fortunately, our replication-competent Ad 11p vector might solve this problem. Regarding the use of Ad-vector candidates for vaccine purposes, this study demonstrates the selection of animal cell lines and determination of suitable virus doses in in vitro experiments.

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  • 21.
    Gwon, Yong-Dae
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Strand, Mårten
    Lindquist, Richard
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Saleeb, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Antiviral Activity of Benzavir-2 against Emerging Flaviviruses2020In: Viruses, E-ISSN 1999-4915, Vol. 12, no 3, article id 351Article in journal (Refereed)
    Abstract [en]

    Most flaviviruses are arthropod-borne viruses, transmitted by either ticks or mosquitoes, and cause morbidity and mortality worldwide. They are endemic in many countries and have recently emerged in new regions, such as the Zika virus (ZIKV) in South-and Central America, the West Nile virus (WNV) in North America, and the Yellow fever virus (YFV) in Brazil and many African countries, highlighting the need for preparedness. Currently, there are no antiviral drugs available to treat flavivirus infections. We have previously discovered a broad-spectrum antiviral compound, benzavir-2, with potent antiviral activity against both DNA- and RNA-viruses. Our purpose was to investigate the inhibitory activity of benzavir-2 against flaviviruses. We used a ZIKV ZsGreen-expressing vector, two lineages of wild-type ZIKV, and other medically important flaviviruses. Benzavir-2 inhibited ZIKV derived reporter gene expression with an EC50 value of 0.8 +/- 0.1 µM. Furthermore, ZIKV plaque formation, progeny virus production, and viral RNA expression were strongly inhibited. In addition, 2.5 µM of benzavir-2 reduced infection in vitro in three to five orders of magnitude for five other flaviviruses: WNV, YFV, the tick-borne encephalitis virus, Japanese encephalitis virus, and dengue virus. In conclusion, benzavir-2 was a potent inhibitor of flavivirus infection, which supported the broad-spectrum antiviral activity of benzavir-2.

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  • 22.
    Haid, Sibylle
    et al.
    Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
    Matthaei, Alina
    Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
    Winkler, Melina
    Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
    Sake, Svenja M.
    Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
    Gunesch, Antonia P.
    Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
    Milke, Vanessa
    Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
    Köhler, Natalie M.
    Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
    Rückert, Jessica
    Institute of Virology, Hannover Medical School, Hannover, Germany; German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany.
    Vieyres, Gabrielle
    Junior Research Group “Cell Biology of RNA Viruses”, Leibniz Institute of Experimental Virology, Hamburg, Germany; Integrative Analysis of Pathogen-Induced Compartments, Leibniz ScienceCampus InterACt, Hamburg, Germany.
    Kühl, David
    Junior Research Group “Cell Biology of RNA Viruses”, Leibniz Institute of Experimental Virology, Hamburg, Germany.
    Nguyen, Tu-Trinh
    Calibr, a Division, The Scripps Research Institute, La Jolla, CA, United States.
    Göhl, Matthias
    German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany; Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Lasswitz, Lisa
    Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry, Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Zapatero-Belinchón, Francisco J.
    Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry, Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Brogden, Graham
    Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry, Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry, Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
    Wiegmann, Bettina
    Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany; Lower Saxony Center for Biomedical Engineering, Implant Research and Development, Hannover Medical School, Hannover, Germany; BREATH (Biomedical Research in Endstage and Obstructive Lung Disease Hannover), German Center for Lung Research (DZL), Carl-Neuberg Str. 1, Hannover, Germany.
    Bilitewski, Ursula
    Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Brown, Richard J.P.
    Division of Veterinary Medicine, Paul Ehrlich Institute, Langen, Germany; Department of Molecular and Medical Virology, Ruhr University, Bochum, Germany.
    Brönstrup, Mark
    German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany; Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Schulz, Thomas F.
    Institute of Virology, Hannover Medical School, Hannover, Germany; German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
    Pietschmann, Thomas
    Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany; German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
    Repurposing screen identifies novel candidates for broad-spectrum coronavirus antivirals and druggable host targets2024In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 68, no 3, article id e01210-23Article in journal (Refereed)
    Abstract [en]

    Libraries composed of licensed drugs represent a vast repertoire of molecules modulating physiological processes in humans, providing unique opportunities for the discovery of host-targeting antivirals. We screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) repurposing library with approximately 12,000 molecules for broad-spectrum coronavirus antivirals and discovered 134 compounds inhibiting an alphacoronavirus and mapping to 58 molecular target categories. Dominant targets included the 5-hydroxytryptamine receptor, the dopamine receptor, and cyclin-dependent kinases. Gene knock-out of the drugs’ host targets including cathepsin B and L (CTSB/L; VBY-825), the aryl hydrocarbon receptor (AHR; Phortress), the farnesyl-diphosphate farnesyltransferase 1 (FDFT1; P-3622), and the kelch-like ECH-associated protein 1 (KEAP1; Omaveloxolone), significantly modulated HCoV-229E infection, providing evidence that these compounds inhibited the virus through acting on their respective host targets. Counter-screening of all 134 primary compound candidates with SARS-CoV-2 and validation in primary cells identified Phortress, an AHR activating ligand, P-3622-targeting FDFT1, and Omaveloxolone, which activates the NFE2-like bZIP transcription factor 2 (NFE2L2) by liberating it from its endogenous inhibitor KEAP1, as antiviral candidates for both an Alpha- and a Betacoronavirus. This study provides an overview of HCoV-229E repurposing candidates and reveals novel potentially druggable viral host dependency factors hijacked by diverse coronaviruses.

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  • 23.
    Hemmingsson, Eva-Stina
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Hjelmare, Ellen
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Weidung, Bodil
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Department of Public Health and Caring Sciences, Geriatric Medicine, Uppsala University, Uppsala, Sweden.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Antiviral treatment associated with reduced risk of clinical Alzheimer's disease: A nested case-control study2021In: Alzheimer’s & Dementia: Translational Research & Clinical Interventions, E-ISSN 2352-8737, Vol. 7, no 1, article id e12187Article in journal (Refereed)
    Abstract [en]

    Introduction: In this nested case-control study, we investigated if antiviral treatment given prior to onset of Alzheimer's disease (AD) could influence incident AD.

    Methods: From a large population-based cohort study in northern Sweden, 262 individuals that later developed AD were compared to a non-AD matched control group with respect to prescriptions of herpes antiviral treatment. All included subjects were herpes simplex virus 1 (HSV1) carriers and the matching criteria were age, sex, apolipoprotein E genotype (ε4 allele carriership), and study sample start year.

    Results: Among those who developed AD, 6 prescriptions of antivirals were found, compared to 20 among matched controls. Adjusted for length of follow-up, a conditional logistic regression indicated a difference in the risk for AD development between groups (odds ratio for AD with an antiviral prescription 0.287, P = .018).

    Discussion: Antiviral treatment might possibly reduce the risk for later development of HSV1-associated AD.

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  • 24. Herrmann, Björn
    et al.
    Söderqvist, Joakim
    Stark, Lisa
    Gullsby, Karolina
    Karlsson, Roger
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Wikman, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Chlamydia trachomatis testing: a national evaluation of internet based self-sampling in sweden2019In: Sexually Transmitted Infections, ISSN 1368-4973, E-ISSN 1472-3263, Vol. 95, p. A72-A72Article in journal (Other academic)
    Abstract [en]

    Background Chlamydia trachomatis (CT) testing in Sweden is free of charge and now exceeds 600,000 annual tests in a population of 10 million. These tests include internet-based self-sampling tests, a service that gradually has been implemented as a part of routine diagnostics in all 21 counties. To our knowledge Sweden is the country with the highest coverage of internet based self-sampling for CT. This study evaluates the diagnostic outcome for self-sampling.

    Methods Requests for both self-sampling at home and clinic based sampling for CT-testing were sent to the laboratories in 18 of 21 counties. All 18 counties provided data on self-sampling in 2017 and 12 counties (representing 80% of the population) provided data on both self-collected samples at home and clinic based testing for the years 2013 to 2017.

    Results The proportion of self-sampling increased from 12.9% in 2013 to 17.8% in 2016 when compared to national chlamydia test figures. Between 23% and 26% of delivered test kits were never sent back for analysis during 2013–2017. In analysis of 12 counties self-sampling increased by 110% between 2013 (n=32,993) and 2017 (n=69,181) for women, compared to 67% for men (2013: n=21,008; 2017: n=35,091). Test volumes for clinic based sampling was fairly constant for both sexes (women 2013 n=245,274; 2017 n=243,338; men 2013 n=97,519; 2017 n=110,617). The proportion of men was 36% for self-sampling compared to 30% (p<0,00001) for clinic based sampling, and the positivity rate decreased for both groups from 2013 to 2017 (7,8% to 7,1% (p<0,01)) vs 9.1% to 7.0% (p<0,0001)). Corresponding figures for women went from 5.3% to 4.6% (p<0,0001)and from 4.9% to 4.1% (p<0,0001).

    Conclusion Self-sampling has increased significantly in recent years, especially among women.

    The positivity rate is similar in self-collected and clinic collected samples.

    Self-sampling reaches men more than clinic based testing, but not as much as expected.

    Disclosure No significant relationships.

  • 25.
    Holm, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Eriksson, Irene
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Laurell, G.
    Department of Surgical Sciences, Division of Otorhinolaryngology, Uppsala Universit, Uppsala, Sweden.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Absence de papillomavirus humain à risque élevé dans le papillome inversé naso-sinusien p16 positif: [Absence of high-risk human papillomavirus in p16 positive inverted sinonasal papilloma]2020In: Annales Francaises d'Oto-Rhino-Laryngologie et de Pathologie Cervico-Faciale, ISSN 1879-7261, Vol. 137, no 3, p. 186-191Article in journal (Refereed)
    Abstract [fr]

    Le papillome inversé naso-sinusien (PINS) est une tumeur relativement rare dont l’étiologie est mal connue. Elle se caractérise par une agressivité locale et un fort potentiel de récidive en dépit d’une histologie bénigne.

    Objectif: L’objectif de cette étude était d’identifier la présence du papillomavirus humain (HPV) et de son marqueur de substitution, la protéine p16, dans des prélèvements tissulaires de PINS issus d’une cohorte régionale.

    Matériels et méthodes: À partir de notre cohorte régionale de 88 patients atteints de PINS traités entre 1984 et 2014, 54 sujets ont été sélectionnés et inclus dans cette étude. La technologie PCR a été réalisée sur 53 prélèvements et la coloration immunohistochimique pour recherche de p16 a été réalisée sur 54 prélèvements. L’ADN a été extrait après confirmation histopathologique du PINS. Un génotypage pour 13 types de HPV à risque élevé, 5 types de HPV à risque oncogène et 6 types de HPV à faible risque a été réalisé à l’aide du test de dépistage HPV PapilloCheck®.

    Résultats: L’analyse HPV a été réalisable sur 38 des 53 prélèvements. Sur ces 38 prélèvements, seuls 2 étaient positifs pour HPV 11. L’analyse immunohistochimique a montré que p16 était présent dans l’épithélium de tous les prélèvements, et dans les régions papillomateuses de 37 prélèvements.

    Conclusion: Étant donné que seuls 2 sur 38 PINS étaient positifs pour HPV (type 11) et que, dans le même temps, p16 était positif dans l’épithélium de tous les prélèvements et dans 37 des 38 régions papillomateuses, nous avons conclu que p16 ne peut pas être utilisé comme marqueur de substitution pour l’infection HPV à risque élevé dans le PINS. Nous préparons actuellement une étude multicentrique prospective afin d’augmenter la puissance de l’étude et de pouvoir mieux évaluer les implications cliniques de HPV et de p16 dans le PINS.

  • 26.
    Holm, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Schindele, Alexandra
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Östersunds hospital, Sweden.
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Eriksson, Irene
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Sandström, Karl
    Laurell, Göran
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Mapping of Human Papilloma Virus, p16, and Epstein-Barr Virusin Non-Malignant Tonsillar Disease2019In: Laryngoscope Investigative Otolaryngology (LIO), E-ISSN 2378-8038, Vol. 4, no 3, p. 285-291Article in journal (Refereed)
    Abstract [en]

    Objectives: Due to their location in the entrance of the aero‐digestive tract, tonsils are steadily exposed to viruses. Human papilloma virus (HPV) and Epstein‐Barr virus (EBV) are two potentially oncogenic viruses that tonsils encounter. The incidence of HPV positive tonsillar cancer is on the rise and it is unknown when infection with HPV occurs.

    Aim: To investigate if tonsils are infected with HPV and EBV, to study the co‐expression of HPV and its surrogate marker p16, and to evaluate the number of EBV positive cells in benign tonsillar disease.

    Materials and Methods: Tonsils from 40 patients in a university hospital were removed due to hypertrophy, chronic or recurrent infection. These were analyzed for presence of HPV, its surrogate marker p16, and EBV. HPV was studied using PapilloCheck (a PCR method), while p16 was identified in epithelial and lymphoid tissue with immunohistochemistry and EBV using EBER‐ISH (Epstein‐Barr encoding region–in situ hybridization).

    Results: HPV was not detected, and p16 was present at low numbers in all epithelial samples as well as in 92.5% of the lymphoid tonsillar samples. At least one EBER‐positive cell was seen in 65% of cases. Larger numbers of EBER‐expressing cells were only seen in two cases.

    Conclusion: These findings demonstrate that EBV and HPV infect tonsils independently, but further studies are warranted to confirm their infectious relationship.

    Level of Evidence: Cross‐sectional study

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  • 27.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jurstrand, Margaretha
    Clinical Research Centre, Örebro University Hospital, Örebro, Sweden.
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Chlamydia trachomatis and Mycoplasma genitalium plasma antibodies in relation to epithelial ovarian tumors2011In: Infectious diseases in obstetrics and gynecology, ISSN 1064-7449, E-ISSN 1098-0997, Vol. 2011, article id 824627Article in journal (Refereed)
    Abstract [en]

    Objective: To assess associations of Chlamydia trachomatis and Mycoplasma genitalium antibodies with epithelial ovarian tumors.

    Methods: Plasma samples from 291 women, undergoing surgery due to suspected ovarian pathology, were analyzed with respect to C. trachomatis IgG and IgA, chlamydial Heat Shock Protein 60-1 (cHSP60-1) IgG and M. genitalium IgG antibodies. Women with borderline tumors (), ovarian carcinoma (), or other pelvic malignancies () were matched to four healthy controls each.

    Results: Overall, there were no associations of antibodies with EOC. However, chlamydial HSP60-1 IgG antibodies were associated with type II ovarian cancer () in women with plasma samples obtained >1 year prior to diagnosis (). M. genitalium IgG antibodies were associated with borderline ovarian tumors ().

    Conclusion: Chlamydial HSP60-1 IgG and M. genitalium IgG antibodies are in this study associated with epithelial ovarian tumors in some subsets, which support the hypothesis linking upper-genital tract infections and ovarian tumor development.

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  • 28.
    Jiang, Hui
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Department of Molecular Biosciences, The Wenner–Gren Institute, Stockholm University, Stockholm, Sweden.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    [RETRACTED] Sars–cov–2 spike impairs dna damage repair and inhibits V(D)J recombination in vitro2021In: Viruses, E-ISSN 1999-4915, Vol. 13, no 10, article id 2056Article in journal (Refereed)
    Abstract [en]

    Paper retracted.

  • 29.
    Johansson, Emil
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Caraballo, Remi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hurdiss, Daniel L.
    Virology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.
    Mistry, Nitesh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thompson, Rebecca F.
    Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
    Ranson, Neil A.
    Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
    Zocher, Georg
    Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
    Stehle, Thilo
    Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany; Department of Pediatrics, Vanderbilt University School of Medicine, TN, Nashville, United States.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Exploring the effect of structure-based scaffold hopping on the inhibition of coxsackievirus a24v transduction by pentavalent n-acetylneuraminic acid conjugates2021In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 16, article id 8418Article in journal (Refereed)
    Abstract [en]

    Coxsackievirus A24 variant (CVA24v) is the primary causative agent of the highly contagious eye infection designated acute hemorrhagic conjunctivitis (AHC). It is solely responsible for two pandemics and several recurring outbreaks of the disease over the last decades, thus affecting millions of individuals throughout the world. To date, no antiviral agents or vaccines are available for combating this disease, and treatment is mainly supportive. CVA24v utilizes Neu5Ac-containing glycans as attachment receptors facilitating entry into host cells. We have previously reported that pentavalent Neu5Ac conjugates based on a glucose-scaffold inhibit CVA24v infection of human corneal epithelial cells. In this study, we report on the design and synthesis of scaffold-replaced pentavalent Neu5Ac conjugates and their effect on CVA24v cell transduction and the use of cryogenic electron microscopy (cryo-EM) to study the binding of these multivalent conjugates to CVA24v. The results presented here provide insights into the development of Neu5Ac-based inhibitors of CVA24v and, most significantly, the first application of cryo-EM to study the binding of a multivalent ligand to a lectin.

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  • 30.
    Johansson, Emil
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Caraballo, Remi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mistry, Nitesh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Zocher, Georg
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hurdiss, Daniel L.
    Chandra, Naresh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Thompson, Rebecca
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Stehle, Thilo
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Pentavalent Sialic Acid Conjugates Block Coxsackievirus A24 Variant and Human Adenovirus Type 37-Viruses That Cause Highly Contagious Eye Infections2020In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 15, no 10, p. 2683-2691Article in journal (Refereed)
    Abstract [en]

    Coxsackievirus A24 variant (CVA24v) and human adenovirus 37 (HAdV-37) are leading causative agents of the severe and highly contagious ocular infections acute hemorrhagic conjunctivitis and epidemic keratoconjunctivitis, respectively. Currently, neither vaccines nor antiviral agents are available for treating these diseases, which affect millions of individuals worldwide. CVA24v and HAdV-37 utilize sialic acid as attachment receptors facilitating entry into host cells. Previously, we and others have shown that derivatives based on sialic acid are effective in preventing HAdV-37 binding and infection of cells. Here, we designed and synthesized novel pentavalent sialic acid conjugates and studied their inhibitory effect against CVA24v and HAdV-37 binding and infection of human corneal epithelial cells. The pentavalent conjugates are the first reported inhibitors of CVA24v infection and proved efficient in blocking HAdV-37 binding. Taken together, the pentavalent conjugates presented here form a basis for the development of general inhibitors of these highly contagious ocular pathogens.

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  • 31.
    Jonsson, S.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Idahl, A.
    Chlamydia trachomatis and anti-MUC1 antibodies and subsequent risk of high grade serous ovarian cancer: a population-based case-control study in Northern Sweden2019In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 29, p. A139-A139Article in journal (Other academic)
    Abstract [en]

    Introduction/Background Chlamydia trachomatis (C. trachomatis) salpingitis causes inflammatory damage to the fallopian tube, the suggested origin of most high grade serous cancers (HGSC), and could thereby cause initiation and progression of ovarian cancer. Infection with C. trachomatis may stimulate production of MUC1 protein and potentially both increase or decrease anti-MUC1 antibody levels. The aim of this study was to examine if serology indicating past infection with C. trachomatis and anti-MUC1 antibodies in prospective blood samples were associated with HGSC.

    Methodology In a prospective nested case-control study within the Northern Sweden Health and Disease Study (NSHDS) and the Northern Sweden Maternity Cohort (NSMC), the prevalence of chlamydial and anti-MUC1 antibodies was analyzed in blood samples drawn more than one year prior to diagnosis from 92 women with HGSC and 363 matched controls. Matching factors were age and date at blood draw. Plasma C. trachomatis IgG was analyzed using a MIF-test (Focus Diagnostics), chlamydial HSP60 (cHSP60) and anti-MUC1 IgG were analyzed using ELISA serology (Medac; Thermo-Fisher Scientific). HGSC diagnosis was confirmed by pathology report review.

    Data were analyzed using Chi-square test, Fisher’s exact test and Mann-Whitney U test. Correlation analysis was done by Spearman’s correlation test. A two-sided P-value less than 0.05 was considered significant.

    Results The prevalence of C. trachomatis IgG and cHSP60 IgG antibodies, as well as the level of anti-MUC1 IgG in women with HGSC compared with controls were similar (16.3% vs. 17.0%, p=0.867; 27.3% vs 28.5%, p=0.802; median 0.24 vs 0.25, p=0.700). A significant correlation was found between anti-MUC1 IgG and cHSP60 IgG (r=0.169; p< 0.001).

    Conclusion There were no significant association between chlamydial or anti-MUC1 IgG antibodies and HGSC in this prospective nested case control study.

  • 32. Khalil, Hussein
    et al.
    Ecke, Frauke
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Bucht, Göran
    Hörnfeldt, Birger
    Population Dynamics of Bank Voles Predicts Human Puumala Hantavirus Risk2019In: EcoHealth, ISSN 1612-9202, E-ISSN 1612-9210, Vol. 16, no 3, p. 545-557Article in journal (Refereed)
    Abstract [en]

    Predicting risk of zoonotic diseases, i.e., diseases shared by humans and animals, is often complicated by the population ecology of wildlife host(s). We here demonstrate how ecological knowledge of a disease system can be used for early prediction of human risk using Puumala hantavirus (PUUV) in bank voles (Myodes glareolus), which causes Nephropathia epidemica (NE) in humans, as a model system. Bank vole populations at northern latitudes exhibit multiannual fluctuations in density and spatial distribution, a phenomenon that has been studied extensively. Nevertheless, existing studies predict NE incidence only a few months before an outbreak. We used a time series on cyclic bank vole population density (1972–2013), their PUUV infection rates (1979–1986; 2003–2013), and NE incidence in Sweden (1990–2013). Depending on the relationship between vole density and infection prevalence (proportion of infected animals), either overall density of bank voles or the density of infected bank voles may be used to predict seasonal NE incidence. The density and spatial distribution of voles at density minima of a population cycle contribute to the early warning of NE risk later at its cyclic peak. When bank voles remain relatively widespread in the landscape during cyclic minima, PUUV can spread from a high baseline during a cycle, culminating in high prevalence in bank voles and potentially high NE risk during peak densities.

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  • 33.
    Larsson, Nirina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Ejnestrand, Jennifer
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Lidgren, Yvonne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Boman, Jens
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Are Swedish swingers a risk group for sexually transmitted infections?2021In: International Journal of STD and AIDS (London), ISSN 0956-4624, E-ISSN 1758-1052, Vol. 32, no 5, p. 427-434Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate whether Swedish swingers constitute a risk group for sexually transmitted infections (STIs). Two swinger clubs were invited to participate. At swinger meetings, members were offered an STI sampling kit and a questionnaire. Samples were analyzed for Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, and Trichomonas vaginalis using a multiplex real-time polymerase chain reaction assay. In total, 235 swingers participated (118 women and 117 men). Urogenital C. trachomatis prevalence was 1.7%. Urogenital M. genitalium prevalence was 7.6% for women and 4.3% for men. No one tested positive for N. gonorrhoeae or T. vaginalis. For women, the mean number of unprotected temporary sex partners within the last 12 months was four men (range 0–35) and three women (range 0–50). Among men, the mean number of unprotected temporary sex partners within the last 12 months was five women (range 0–50) and 0 men (range 0–10). During vaginal sex, 46.6% women and 38.5% men always used protection with a temporary sex partner. Swedish swingers did not seem to have an increased prevalence of STIs. However, there was high-risk sexual behavior with unprotected sex and multiple sex partners, thereby making them a vulnerable group for acquiring STIs.

  • 34.
    Lasswitz, Lisa
    et al.
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hanover, Germany; Institute for Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hanover, Hanover, Germany.
    Zapatero-Belinchón, Francisco J.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hanover, Germany; Institute for Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hanover, Hanover, Germany.
    Moeller, Rebecca
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hanover, Germany; Institute for Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hanover, Hanover, Germany.
    Hülskötter, Kirsten
    Department of Pathology, University of Veterinary Medicine Hanover, Hanover, Germany.
    Laurent, Timothée
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Goffinet, Christine
    Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Virology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany.
    Simmons, Graham
    Vitalant Research Institute, University of California, CA, San Francisco, United States; Department of Laboratory Medicine, University of California, CA, San Francisco, United States.
    Baumgärtner, Wolfgang
    Department of Pathology, University of Veterinary Medicine Hanover, Hanover, Germany.
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hanover, Germany; Institute for Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hanover, Hanover, Germany.
    The tetraspanin CD81 is a host factor for Chikungunya virus replication2022In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 13, no 3, article id e0073122Article in journal (Refereed)
    Abstract [en]

    Chikungunya virus (CHIKV) is an arthritogenic reemerging virus replicating in plasma membrane-derived compartments termed "spherules." Here, we identify the human transmembrane protein CD81 as host factor required for CHIKV replication. Ablation of CD81 results in decreased CHIKV permissiveness, while overexpression enhances infection. CD81 is dispensable for virus uptake but critically required for viral genome replication. Likewise, murine CD81 is crucial for CHIKV permissiveness and is expressed in target cells such as dermal fibroblasts, muscle and liver cells. Whereas related alphaviruses, including Ross River virus (RRV), Semliki Forest virus (SFV), Sindbis virus (SINV) and Venezuelan equine encephalitis virus (VEEV), also depend on CD81 for infection, RNA viruses from other families, such as coronaviruses, replicate independently of CD81. Strikingly, the replication-enhancing function of CD81 is linked to cholesterol binding. These results define a mechanism exploited by alphaviruses to hijack the membrane microdomain-modeling protein CD81 for virus replication through interaction with cholesterol.

    IMPORTANCE: In this study, we discover the tetraspanin CD81 as a host factor for the globally emerging chikungunya virus and related alphaviruses. We show that CD81 promotes replication of viral genomes in human and mouse cells, while virus entry into cells is independent of CD81. This provides novel insights into how alphaviruses hijack host proteins to complete their life cycle. Alphaviruses replicate at distinct sites of the plasma membrane, which are enriched in cholesterol. We found that the cholesterol-binding ability of CD81 is important for its function as an alphavirus host factor. This discovery thus broadens our understanding of the alphavirus replication process and the use of host factors to reprogram cells into virus replication factories.

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  • 35.
    Li, Dandan
    et al.
    Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    Bühler, Melanie
    Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    Runft, Sandra
    Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Department of Biochemistry, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, Hannover, Germany; Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    Marek, Katarzyna
    Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    Baumgärtner, Wolfgang
    Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    Strowig, Till
    Department for Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany; Hannover Medical School, Hannover, Germany.
    Gerhauser, Ingo
    Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    ASC- and caspase-1-deficient C57BL/6 mice do not develop demyelinating disease after infection with Theiler's murine encephalomyelitis virus2023In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, no 1, article id 10960Article in journal (Refereed)
    Abstract [en]

    Theiler's murine encephalomyelitis virus (TMEV) induces an acute polioencephalomyelitis and a chronic demyelinating leukomyelitis in SJL mice. C57BL/6 (B6) mice generally do not develop TMEV-induced demyelinating disease (TMEV-IDD) due to virus elimination. However, TMEV can persist in specific immunodeficient B6 mice such as IFNβ-/- mice and induce a demyelinating process. The proinflammatory cytokines IL-1β and IL-18 are activated by the inflammasome pathway, which consists of a pattern recognition receptor molecule sensing microbial pathogens, the adaptor molecule Apoptosis-associated speck-like protein containing a CARD (ASC), and the executioner caspase-1. To analyze the contribution of the inflammasome pathway to the resistance of B6 mice to TMEV-IDD, ASC- and caspase-1-deficient mice and wild type littermates were infected with TMEV and investigated using histology, immunohistochemistry, RT-qPCR, and Western Blot. Despite the antiviral activity of the inflammasome pathway, ASC- and caspase-1-deficient mice eliminated the virus and did not develop TMEV-IDD. Moreover, a similar IFNβ and cytokine gene expression was found in the brain of immunodeficient mice and their wild type littermates. Most importantly, Western Blot showed cleavage of IL-1β and IL-18 in all investigated mice. Consequently, inflammasome-dependent activation of IL-1β and IL-18 does not play a major role in the resistance of B6 mice to TMEV-IDD.

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  • 36. Liaci, AM
    et al.
    Chandra, Naresh
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Munender, S
    Liu, Y
    Pfenning, V
    Bachmann, P
    Caraballo, R
    Chai, W
    Johansson, E
    Cupelli, K
    Hassemer, T
    Blaum, B
    Elofsson, M
    Feizi, T
    Arnberg, N
    Stehle, T
    Primary attachment receptors of human adenovirus type 36Manuscript (preprint) (Other academic)
  • 37.
    Lindquist, Richard
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Weber, Elvira
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Asghar, Naveed
    School of Medical Sciences, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Schreier, Sarah
    Institute of Medical Microbiology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Johansson, Magnus
    School of Medical Sciences, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Dobler, Gerhard
    Bundeswehr Institute of Microbiology, Munich, Germany.
    Bestehorn, Malena
    Bundeswehr Institute of Microbiology, Munich, Germany; Parasitology Unit, University of Hohenheim, D-, Stuttgart, Germany.
    Kröger, Andrea
    Institute of Medical Microbiology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    The envelope protein of tick-borne encephalitis virus influences neuron entry, pathogenicity, and vaccine protection2020In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 17, no 1, article id 284Article in journal (Refereed)
    Abstract [en]

    Background: Tick-borne encephalitis virus (TBEV) is considered to be the medically most important arthropod-borne virus in Europe. The symptoms of an infection range from subclinical to mild flu-like disease to lethal encephalitis. The exact determinants of disease severity are not known; however, the virulence of the strain as well as the immune status of the host are thought to be important factors for the outcome of the infection. Here we investigated virulence determinants in TBEV infection.

    Method: Mice were infected with different TBEV strains, and high virulent and low virulent TBEV strains were chosen. Sequence alignment identified differences that were cloned to generate chimera virus. The infection rate of the parental and chimeric virus were evaluated in primary mouse neurons, astrocytes, mouse embryonic fibroblasts, and in vivo. Neutralizing capacity of serum from individuals vaccinated with the FSME-IMMUN® and Encepur® or combined were evaluated.

    Results: We identified a highly pathogenic and neurovirulent TBEV strain, 93/783. Using sequence analysis, we identified the envelope (E) protein of 93/783 as a potential virulence determinant and cloned it into the less pathogenic TBEV strain Torö. We found that the chimeric virus specifically infected primary neurons more efficiently compared to wild-type (WT) Torö and this correlated with enhanced pathogenicity and higher levels of viral RNA in vivo. The E protein is also the major target of neutralizing antibodies; thus, genetic variation in the E protein could influence the efficiency of the two available vaccines, FSME-IMMUN® and Encepur®. As TBEV vaccine breakthroughs have occurred in Europe, we chose to compare neutralizing capacity from individuals vaccinated with the two different vaccines or a combination of them. Our data suggest that the different vaccines do not perform equally well against the two Swedish strains.

    Conclusions: Our findings show that two amino acid substitutions of the E protein found in 93/783, A83T, and A463S enhanced Torö infection of neurons as well as pathogenesis and viral replication in vivo; furthermore, we found that genetic divergence from the vaccine strain resulted in lower neutralizing antibody titers in vaccinated individuals.

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  • 38.
    Lopatko Lindman, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Hemmingsson, Eva-Stina
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Weidung, Bodil
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Department of Public Health and Caring Sciences, Geriatric Medicine, Uppsala University, Uppsala, Sweden.
    Brännström, Jon
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Herpesvirus infections, antiviral treatment, and the risk ofdementia: a registry-based cohort study in Sweden2021In: Alzheimer’s & Dementia: Translational Research & Clinical Interventions, E-ISSN 2352-8737, Vol. 7, no 1, article id e12119Article in journal (Refereed)
    Abstract [en]

    Introduction: Herpesviruses, including Herpes simplex virus type 1 (HSV1) and varicella zoster‐virus (VZV), have been implicated in Alzheimer's disease (AD) development. Likewise, antiviral treatment has been suggested to protect against dementia development in herpes‐infected individuals.

    Methods: The study enrolled 265,172 subjects aged ≥ 50 years, with diagnoses of VZV or HSV, or prescribed antiviral drugs between 31 December 2005 and 31 December 2017. Controls were matched in a 1:1 ratio by sex and birth year.

    Results: Antiviral treatment was associated with decreased risk of dementia (adjusted hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.86 to 0.92), while herpes infection without antiviral drugs increased the risk of dementia (adjusted HR 1.50, 95% CI 1.29 to 1.74).

    Discussion: Antiviral treatment was associated with a reduced long‐term risk of dementia among individuals with overt signs of herpes infection. This is consistent with earlier findings indicating that herpesviruses are involved in the pathogenesis of AD.

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  • 39.
    Lopatko Lindman, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Weidung, Bodil
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Department of Public Health and Caring Sciences, Geriatric Medicine, Uppsala University, Uppsala, Sweden.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Plasma Amyloid-β in Relation to Antibodies Against Herpes Simplex Virus, Cytomegalovirus, and Chlamydophila pneumoniae2021In: Journal of Alzheimer's Disease Reports, E-ISSN 2542-4823, Vol. 5, no 1, p. 229-235Article in journal (Refereed)
    Abstract [en]

    Background: Amyloid-β (Aβ), the key constituent of Alzheimer’s disease (AD) plaques, has antimicrobial properties.

    Objective: To investigate the association between plasma Aβ and antibodies against the AD-related pathogens herpes simplex virus (HSV), cytomegalovirus (CMV), and C. pneumoniae.

    Methods: Plasma from 339 AD cases, obtained on average 9.4 years (±4.00) before diagnosis, and their matched controls were analyzed for Aβ40 and Aβ42 concentrations with Luminex xMAP technology and INNOBIA plasma Aβ-form assays. Enzyme-linked immunosorbent assays were utilized for analyses of anti-HSV immunoglobulin (Ig) G, anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae IgG. Follow-up samples were available for 150 of the cases.

    Results: Presence and levels of anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae IgG did not correlate with concentrations of Aβ42 or Aβ40 in cases or controls.

    Conclusion: Levels of plasma Aβ were not associated with antibodies against different AD-related pathogens.

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  • 40.
    Lopatko Lindman, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Weidung, Bodil
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Department of Public Health and Caring Sciences, Geriatric Medicine, Uppsala University, Uppsala, Sweden.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Kok, Eloise
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    A genetic signature including apolipoprotein Eε4 potentiates the risk of herpes simplex-associated Alzheimer's disease2019In: Alzheimer’s & Dementia: Translational Research & Clinical Interventions, E-ISSN 2352-8737, Vol. 5, p. 697-704Article in journal (Refereed)
    Abstract [en]

    Introduction: Herpes simplex virus type 1 (HSV1) in combination with genetic susceptibility has previously been implicated in Alzheimer's disease (AD) pathogenesis.

    Methods: Plasma from 360 AD cases, obtained on average 9.6 years before diagnosis, and their age- and sex-matched controls, were analyzed for anti-HSV1 immunoglobulin (Ig) G with enzyme-linked immunosorbent assays (ELISAs). APOE genotype and nine other selected risk genes for AD were extracted from a genome-wide association study analysis by deCODE genetics, Reykjavik, Iceland.

    Results: The interaction between APOEε4 heterozygosity (APOEε24 or ε3/ε4) and anti-HSV1 IgG carriage increased the risk of AD (OR 4.55, P = .02). A genetic risk score based on the nine AD risk genes also interacted with anti-HSV1 IgG for the risk of developing AD (OR 2.35, P = .01).

    Discussion: The present findings suggest that the APOEε4 allele and other AD genetic risk factors might potentiate the risk of HSV1-associated AD.

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  • 41. Luande, Verah Nafula
    et al.
    Eklöf, Disa
    Lindström, Anders
    Nyanjom, Steven Ger
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Lilja, Tobias
    The Human Biting Culex pipiens Bioform molestus Detected in Several Areas in Southern Sweden2020In: Vector Borne and Zoonotic Diseases, ISSN 1530-3667, E-ISSN 1557-7759, Vol. 20, no 12, p. 936-938Article in journal (Refereed)
    Abstract [en]

    Background: The mosquito species Culex pipiens is a known vector of several pathogens and occurs in two distinct bioforms, pipiens and molestus. The bioform molestus thrives in urban environments where there are below-ground habitats; it can mate in confined spaces and feed on mammals as well as birds. In contrast, the bioform pipiens is found above ground, is thought to require more space for mating, and mainly feeds on birds. The pipiens bioform is present in large parts of Sweden but the molestus bioform has previously only been found in major cities.

    Materials and Methods: People experiencing mosquito nuisance in southern Sweden submitted mosquito samples as part of a citizen science project, and these samples were analyzed to determine the geographical distribution of the molestus bioform of Cx. pipiens. Mosquito specimens were identified to the species level by DNA barcoding of the cytochrome C oxidase subunit I (COI) gene, and the bioforms were determined through the CQ11 microsatellite marker.

    Results:Culex pipiens f molestus was observed to be spread across large parts of Gothenburg as well as in the suburbs. This bioform was found both in urban and rural areas at several sites across southern Sweden. In one site, hybrids between the two bioforms were found.

    Conclusions: The detection of Cx. pipiens f molestus in several rural areas was surprising, indicating that it may be more widely spread than urban areas alone, where it has been previously reported.

  • 42.
    Lwande, Olivia Wesula
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Mohamed, Nahla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Bucht, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Olsson, Gert
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Seewis hantavirus in common shrew (Sorex araneus) in Sweden2020In: Virology Journal, E-ISSN 1743-422X, Vol. 17, no 1, article id 198Article in journal (Refereed)
    Abstract [en]

    Background: Rodent borne hantaviruses are emerging viruses infecting humans through inhalation. They cause hemorrhagic fever with renal syndrome and hemorrhagic cardiopulmonary syndrome. Recently, hantaviruses have been detected in other small mammals such as Soricomorpha (shrews, moles) and Chiroptera (bats), suggested as reservoirs for potential pandemic viruses and to play a role in the evolution of hantaviruses. It is important to study the global virome in different reservoirs, therefore our aim was to investigate whether shrews in Sweden carried any hantaviruses. Moreover, to accurately determine the host species, we developed a molecular method for identification of shrews.

    Method: Shrews (n = 198), caught during 1998 in Sweden, were screened with a pan-hantavirus PCR using primers from a conserved region of the large genome segment. In addition to morphological typing of shrews, we developed a molecular based typing method using sequencing of the mitochondrial cytochrome C oxidase I (COI) and cytochrome B (CytB) genes. PCR amplified hantavirus and shrew fragments were sequenced and phylogenetically analysed.

    Results: Hantavirus RNA was detected in three shrews. Sequencing identified the virus as Seewis hantavirus (SWSV), most closely related to previous isolates from Finland and Russia. All three SWSV sequences were retrieved from common shrews (Sorex araneus) sampled in Västerbotten County, Sweden. The genetic assay for shrew identification was able to identify native Swedish shrew species, and the genetic typing of the Swedish common shrews revealed that they were most similar to common shrews from Russia.

    Conclusion: We detected SWSV RNA in Swedish common shrew samples and developed a genetic assay for shrew identification based on the COI and CytB genes. This was the first report of presence of hantavirus in Swedish shrews.

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  • 43.
    Lwande, Olivia Wesula
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Arctic Research Centre at Umeå University.
    Näslund, Jonas
    Lundmark, Eva
    Ahlm, Kristoffer
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ahlm, Clas
    Umeå University, Arctic Research Centre at Umeå University. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Bucht, Göran
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Arctic Research Centre at Umeå University.
    Experimental Infection and Transmission Competence of Sindbis Virus in Culex torrentium and Culex pipiens Mosquitoes from Northern Sweden2019In: Vector Borne and Zoonotic Diseases, ISSN 1530-3667, E-ISSN 1557-7759, Vol. 19, no 2, p. 128-133Article in journal (Refereed)
    Abstract [en]

    Introduction: Sindbis virus (SINV) is a mosquito-borne Alphavirus known to infect birds and cause intermittent outbreaks among humans in Fenno-Scandia. In Sweden, the endemic area has mainly been in central Sweden. Recently, SINV infections have emerged to northern Sweden, but the vectorial efficiency for SINV of mosquito species in this northern region has not yet been ascertained.

    Objective: Mosquito larvae were sampled from the Umea region in northern Sweden and propagated in a laboratory to adult stage to investigate the infection, dissemination, and transmission efficiency of SINV in mosquitoes.

    Materials and Methods: The mosquito species were identified by DNA barcoding of the cytochrome oxidase I gene. Culex torrentium was the most abundant (82.2%) followed by Culex pipiens (14.4%), Aedes annulipes (1.1%), Anopheles claviger (1.1%), Culiseta bergrothi (1.1%), or other unidentified species (1.1%). Mosquitoes were fed with SINV-infected blood and monitored for 29 days to determine the viral extrinsic incubation period. Infection and dissemination were determined by RT-qPCR screening of dissected body parts of individual mosquitoes. Viral transmission was determined from saliva collected from individual mosquitoes at 7, 14, and 29 days. SINV was detected by cell culture using BHK-21 cells, RT-qPCR, and sequencing.

    Results: Cx. torrentium was the only mosquito species in our study that was able to transmit SINV. The overall transmission efficiency of SINV in Cx. torrentium was 6.8%. The rates of SINV infection, dissemination, and transmission in Cx. torrentium were 11%, 75%, and 83%, respectively.

    Conclusions: Cx. torrentium may be the key vector involved in SINV transmission in northern Sweden.

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  • 44.
    Lövheim, Hugo
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Norman, Tove
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Weidung, Bodil
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Department of Public Health and Caring Sciences, Geriatric Medicine, Uppsala University, Sweden.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Herpes Simplex Virus, APOE ɛ4, and Cognitive Decline in Old Age: Results from the Betula Cohort Study2019In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 67, no 1, p. 211-220Article in journal (Refereed)
    Abstract [en]

    Background: Herpes simplex virus (HSV) has been suggested to play a role in Alzheimer’s disease (AD) development.

    Objective: The aim of the present study was to investigate the early AD-related symptom episodic memory decline in relation to HSV and carriage of allele 4 of the apolipoprotein E gene (APOE ɛ4) in a large population-based cohort with a long follow-up time.

    Methods: The study included 3,413 persons, with longitudinal data available for 1,293 persons with a mean follow-up time of 11.6 years. The associations between HSV carriage, APOE ɛ4 carriage, and episodic memory was investigated at baseline, as well as in longitudinal analyses where individuals with and without HSV antibodies (HSV1/2 non-specific) were matched and episodic memory decline compared.

    Results: Cross-sectional analyses revealed an age-dependent association of HSV carriage with lower episodic memory function, particularly among APOE ɛ4 carriers (p = 0.008). Longitudinal analyses showed an increased risk of episodic memory decline in HSV carriers (≥65 years: p < 0.001, all ages: non-significant), and a significant interaction between HSV and APOE ɛ4 for episodic memory decline (p < 0.001).

    Conclusion: In this large population-based cohort study, both cross-sectional and longitudinal results support an association between HSV carriage and declining episodic memory function, especially among APOE ɛ4 carriers. The results strengthen the hypothesis that HSV is associated with AD development.

  • 45.
    Marek, Katarzyna
    et al.
    Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany; Center for Systems Neuroscience, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    Armando, Federico
    Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    Asawapattanakul, Thanaporn
    Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany; Center for Systems Neuroscience, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    Nippold, Vanessa Maria
    Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    Plattet, Philippe
    Division of Experimental Clinical Research, Vetsuisse University Bern, Bern, Switzerland.
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Department of Biochemistry, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany; Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    Baumgärtner, Wolfgang
    Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany; Center for Systems Neuroscience, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    Puff, Christina
    Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
    Functional Granulocyte–Macrophage Colony-Stimulating Factor (GM-CSF) Delivered by Canine Histiocytic Sarcoma Cells Persistently Infected with Engineered Attenuated Canine Distemper Virus2023In: Pathogens, E-ISSN 2076-0817, Vol. 12, no 7, article id 877Article in journal (Refereed)
    Abstract [en]

    The immune response plays a key role in the treatment of malignant tumors. One important molecule promoting humoral and cellular immunity is granulocyte–macrophage colony-stimulating factor (GM-CSF). Numerous successful trials have led to the approval of this immune-stimulating molecule for cancer therapy. However, besides immune stimulation, GM-CSF may also accelerate tumor cell proliferation, rendering this molecule a double-edged sword in cancer treatment. Therefore, detailed knowledge about the in vitro function of GM-CSF produced by infected tumor cells is urgently needed prior to investigations in an in vivo model. The aim of the present study was to functionally characterize a persistent infection of canine histiocytic sarcoma cells (DH82 cells) with the canine distemper virus strain Onderstepoort genetically engineered to express canine GM-CSF (CDV-Ondneon-GM-CSF). The investigations aimed (1) to prove the overall functionality of the virally induced production of GM-CSF and (2) to determine the effect of GM-CSF on the proliferation and motility of canine HS cells. Infected cells consistently produced high amounts of active, pH-stable GM-CSF, as demonstrated by increased proliferation of HeLa cells. By contrast, DH82 cells lacked increased proliferation and motility. The significantly increased secretion of GM-CSF by persistently CDV-Ondneon-GM-CSF-infected DH82 cells, the pH stability of this protein, and the lack of detrimental effects on DH82 cells renders this virus strain an interesting candidate for future studies aiming to enhance the oncolytic properties of CDV for the treatment of canine histiocytic sarcomas.

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  • 46.
    Marek, Katarzyna
    et al.
    Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany; Center for Systems Neuroscience, University of Veterinary Medicine Hannover, Hannover, Germany.
    Armando, Federico
    Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.
    Nippold, Vanessa Maria
    Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.
    Rohn, Karl
    Institute for Biometry, Epidemiology and Information Processing, University of Veterinary Medicine Hannover, Hannover, Germany.
    Plattet, Philippe
    Division of Experimental Clinical Research, Vetsuisse University Bern, Bern, Switzerland.
    Brogden, Graham
    Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany; Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany; Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Baumgärtner, Wolfgang
    Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany; Center for Systems Neuroscience, University of Veterinary Medicine Hannover, Hannover, Germany.
    Puff, Christina
    Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.
    Persistent Infection of a Canine Histiocytic Sarcoma Cell Line with Attenuated Canine Distemper Virus Expressing Vasostatin or Granulocyte-Macrophage Colony-Stimulating Factor2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 11, article id 6156Article in journal (Refereed)
    Abstract [en]

    Canine histiocytic sarcoma (HS) represents a neoplasia with poor prognosis. Due to the high metastatic rate of HS, there is urgency to improve treatment options and to prevent tumor metastases. Canine distemper virus (CDV) is a single-stranded negative-sense RNA (ssRNA (-)) virus with potentially oncolytic properties. Moreover, vasostatin and granulocyte-macrophage colony-stimulating factor (GM-CSF) are attractive molecules in cancer therapy research because of their anti-angiogenetic properties and potential modulation of the tumor microenvironment. In the present study, an in vitro characterization of two genetically engineered viruses based on the CDV strain Onderstepoort (CDV-Ond), CDV-Ondneon-vasostatin and CDV-Ondneon-GM-CSF was performed. Canine histiocytic sarcoma cells (DH82 cells) were persistently infected with CDV-Ond, CDV-Ondneon, CDV-Ondneon-vasostatin and CDV-Ondneon-GM-CSF and characterized on a molecular and protein level regarding their vasostatin and GM-CSF production. Interestingly, DH82 cells persistently infected with CDV-Ondneon-vasostatin showed a significantly increased number of vasostatin mRNA transcripts. Similarly, DH82 cells persistently infected with CDV-Ondneon-GM-CSF displayed an increased number of GM-CSF mRNA transcripts mirrored on the protein level as confirmed by immunofluorescence and Western blot. In summary, modified CDV-Ond strains expressed GM-CSF and vasostatin, rendering them promising candidates for the improvement of oncolytic virotherapies, which should be further detailed in future in vivo studies.

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  • 47.
    Matthaei, Alina
    et al.
    Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Lower Saxony, Hannover, Germany.
    Joecks, Sebastian
    Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Lower Saxony, Hannover, Germany.
    Frauenstein, Annika
    RG Experimental Systems Immunology, Max-Planck Institute for Biochemistry, Bavaria, Planegg, Germany.
    Bruening, Janina
    Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Lower Saxony, Hannover, Germany.
    Bankwitz, Dorothea
    Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Lower Saxony, Hannover, Germany.
    Friesland, Martina
    Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Lower Saxony, Hannover, Germany.
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Lower Saxony, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Lower Saxony, Hannover, Germany.
    Vieyres, Gabrielle
    Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Lower Saxony, Hannover, Germany; Junior Research Group "Cell Biology of RNA Viruses, Leibniz Institute of Experimental Virology, Hamburg, Germany.
    Kaderali, Lars
    Institute of Bioinformatics, Greifswald, University Medicine Greifswald, Germany.
    Meissner, Felix
    RG Experimental Systems Immunology, Max-Planck Institute for Biochemistry, Bavaria, Planegg, Germany; Systems Immunology and Proteomics, Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
    Pietschmann, Thomas
    Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Lower Saxony, Hannover, Germany.
    Landscape of protein-protein interactions during hepatitis C virus assembly and release2024In: Microbiology Spectrum, E-ISSN 2165-0497, Vol. 12, no 2, article id e0256222Article in journal (Refereed)
    Abstract [en]

    Assembly of infectious hepatitis C virus (HCV) particles requires multiple cellular proteins including for instance apolipoprotein E (ApoE). To describe these protein-protein interactions, we performed an affinity purification mass spectrometry screen of HCV-infected cells. We used functional viral constructs with epitope-tagged envelope protein 2 (E2), protein (p) 7, or nonstructural protein 4B (NS4B) as well as cells expressing a tagged variant of ApoE. We also evaluated assembly stage-dependent remodeling of protein complexes by using viral mutants carrying point mutations abrogating particle production at distinct steps of the HCV particle production cascade. Five ApoE binding proteins, 12 p7 binders, 7 primary E2 interactors, and 24 proteins interacting with NS4B were detected. Cell-derived PREB, STT3B, and SPCS2 as well as viral NS2 interacted with both p7 and E2. Only GTF3C3 interacted with E2 and NS4B, highlighting that HCV assembly and replication complexes exhibit largely distinct interactomes. An HCV core protein mutation, preventing core protein decoration of lipid droplets, profoundly altered the E2 interactome. In cells replicating this mutant, E2 interactions with HSPA5, STT3A/B, RAD23A/B, and ZNF860 were significantly enhanced, suggesting that E2 protein interactions partly depend on core protein functions. Bioinformatic and functional studies including STRING network analyses, RNA interference, and ectopic expression support a role of Rad23A and Rad23B in facilitating HCV infectious virus production. Both Rad23A and Rad23B are involved in the endoplasmic reticulum (ER)-associated protein degradation (ERAD). Collectively, our results provide a map of host proteins interacting with HCV assembly proteins, and they give evidence for the involvement of ER protein folding machineries and the ERAD pathway in the late stages of the HCV replication cycle.IMPORTANCEHepatitis C virus (HCV) establishes chronic infections in the majority of exposed individuals. This capacity likely depends on viral immune evasion strategies. One feature likely contributing to persistence is the formation of so-called lipo-viro particles. These peculiar virions consist of viral structural proteins and cellular lipids and lipoproteins, the latter of which aid in viral attachment and cell entry and likely antibody escape. To learn about how lipo-viro particles are coined, here, we provide a comprehensive overview of protein-protein interactions in virus-producing cells. We identify numerous novel and specific HCV E2, p7, and cellular apolipoprotein E-interacting proteins. Pathway analyses of these interactors show that proteins participating in processes such as endoplasmic reticulum (ER) protein folding, ER-associated protein degradation, and glycosylation are heavily engaged in virus production. Moreover, we find that the proteome of HCV replication sites is distinct from the assembly proteome, suggesting that transport process likely shuttles viral RNA to assembly sites.

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  • 48.
    Meheretu, Yonas
    et al.
    Department of Biology, Mekelle University, Mekelle, Ethiopia; Institute of Mountain Research & Development, Mekelle University, Mekelle, Ethiopia; Institute of Vertebrate Biology of the Czech Academy of Sciences, Brno, Czech Republic.
    Granberg, Åsa
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Berhane, Gebregiorgis
    Department of Biology, Mekelle University, Mekelle, Ethiopia.
    Khalil, Hussein
    Department of Wildlife, Fish, and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Lwande, Olivia Wesula
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Mitiku, Mengistu
    College Health Sciences, Mekelle University, Mekelle, Ethiopia.
    Welegerima, Kiros
    Department of Biology, Mekelle University, Mekelle, Ethiopia.
    de Bellocq, Joëlle Goüy
    Institute of Vertebrate Biology of the Czech Academy of Sciences, Brno, Czech Republic; Department of Zoology and Fisheries, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences Prague, Prague, Czech Republic.
    Bryja, Josef
    Institute of Vertebrate Biology of the Czech Academy of Sciences, Brno, Czech Republic.
    Abreha, Hagos
    College Health Sciences, Mekelle University, Mekelle, Ethiopia.
    Leirs, Herwig
    Evolutionary Ecology Group, University of Antwerp, Wilrijk, Belgium.
    Ecke, Frauke
    Department of Wildlife, Fish, and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Prevalence of orthohantavirus-reactive antibodies in humans and peri-domestic rodents in northern Ethiopia2021In: Viruses, E-ISSN 1999-4915, Vol. 13, no 6, article id 1054Article in journal (Refereed)
    Abstract [en]

    In 2012, Tigray orthohantavirus was discovered in Ethiopia, but its seasonal infection in small mammals, and whether it poses a risk to humans was unknown. The occurrence of small mammals, rodents and shrews, in human inhabitations in northern Ethiopia is affected by season and presence of stone bunds. We sampled small mammals in two seasons from low-and high-density stone bund fields adjacent to houses and community-protected semi-natural habitats in Atsbi and Hagere Selam, where Tigray orthohantavirus was first discovered. We collected blood samples from both small mammals and residents using filter paper. The presence of orthohantavirus-reactive antibodies in blood was then analyzed using immunofluorescence assay (human samples) and enzyme linked immunosorbent assays (small mammal samples) with Puumala orthohantavirus as antigen. Viral RNA was detected by RT-PCR using small mammal blood samples. Total orthohantavirus prevalence (antibodies or virus RNA) in the small mammals was 3.37%. The positive animals were three Stenocephalemys albipes rats (prevalence in this species = 13.04%). The low prevalence made it impossible to determine whether season and stone bunds were associated with orthohantavirus prevalence in the small mammals. In humans, we report the first detection of orthohantavirus-reactive IgG antibodies in Ethiopia (seroprevalence = 5.26%). S. albipes lives in close proximity to humans, likely increasing the risk of zoonotic transmission.

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  • 49.
    Mhlekude, Baxolele
    et al.
    University of Cape Town, Department of Surgery, Groote Schuur Hospital, Observatory, South Africa; TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Institute of Experimental Virology, Hannover; Charité - Universitätsmedizin Berlin, Institute of Virology, Charité Campus Mitte; Berlin Institute of Health, Berlin, Germany.
    Lenman, Annasara
    TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Institute of Experimental Virology, Hannover.
    Sidoyi, Phikolomzi
    Faculty of Health Sciences, School of Medicine, Walter Sisulu University, Mthatha, South Africa.
    Joseph, Jim
    Department of Human Biology, Walter Sisulu University, Mthatha, South Africa.
    Kruppa, Jochen
    Charité - Universitätsmedizin Berlin, Institut für Biometrie und Klinische Epidemiologie, Charité Campus Mitte, Berlin, Germany.
    Businge, Charles Bitamazire
    Department of Obstetrics and Gynaecology, Walter Sisulu University/Nelson Mandela Academic Hospital.
    Mdaka, Mana Lungisa
    Department of Obstetrics and Gynaecology, Walter Sisulu University/Nelson Mandela Academic Hospital.
    Konietschke, Frank
    Berlin Institute of Health, Berlin, Germany; Charité - Universitätsmedizin Berlin, Institut für Biometrie und Klinische Epidemiologie, Charité Campus Mitte, Berlin, Germany.
    Pich, Andreas
    Hannover Medical School, Institute of Toxicology, Core Facility Proteomics, Hannover, Germany.
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Institute of Experimental Virology, Hannover; Department of Biochemistry, University of Veterinary Medicine Hannover, Hanover, Germany.
    Goffinet, Christine
    TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Institute of Experimental Virology, Hannover; Charité - Universitätsmedizin Berlin, Institute of Virology, Charité Campus Mitte; Berlin Institute of Health, Berlin, Germany.
    Mall, Anwar Suleman
    University of Cape Town, Department of Surgery, Groote Schuur Hospital, Observatory, South Africa.
    The barrier functions of crude cervical mucus plugs against HIV-1 infection in the context of cell-free and cell-to-cell transmission2021In: AIDS, ISSN 0269-9370, E-ISSN 1473-5571, Vol. 35, no 13, p. 2105-2117Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The cervical mucus plugs are enriched with proteins of known immunological functions. We aimed to characterize the anti-HIV-1 activity of the cervical mucus plugs against a panel of different HIV-1 strains in the contexts of cell-free and cell-associated virus.

    DESIGN: A cohort of consenting HIV-1-negative and HIV-1-positive pregnant women in labour was recruited from Mthatha General Hospital in the Eastern Cape province of South Africa, from whom the cervical mucus plugs were collected in 6 M guanidinium chloride with protease inhibitors and transported to our laboratories at -80 °C.

    METHODS: Samples were centrifuged to remove insoluble material and dialysed before freeze--drying and subjecting them to the cell viability assays. The antiviral activities of the samples were studied using luminometric reporter assays and flow cytometry. Time-of-addition and BlaM-Vpr virus-cell fusion assays were used to pin-point the antiviral mechanisms of the cervical mucus plugs, before proteomic profiling using liquid chromatography-tandem mass spectrometry.

    RESULTS: The proteinaceous fraction of the cervical mucus plugs exhibited anti-HIV-1 activity with inter-individual variations and some degree of specificity among different HIV-1 strains. Cell-associated HIV-1 was less susceptible to inhibition by the potent samples whenever compared with the cell-free HIV-1. The samples with high antiviral potency exhibited a distinct proteomic profile when compared with the less potent samples.

    CONCLUSION: The crude cervical mucus plugs exhibit anti-HIV-1 activity, which is defined by a specific proteomic profile.

  • 50.
    Mhlekude, Baxolele
    et al.
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany; Virology and Innate Immunity Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany; Institute of Genetics, Technische Universität Braunschweig, Braunschweig, Germany.
    Postmus, Dylan
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany.
    Stenzel, Saskia
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany.
    Weiner, January
    Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany.
    Jansen, Jenny
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany.
    Zapatero-Belinchón, Francisco J.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany; Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, The Hannover Medical School, The Helmholtz Centre for Infection Research, Hannover, Germany.
    Olmer, Ruth
    Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, REBIRTH—Center for Translational Regenerative Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany.
    Richter, Anja
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
    Heinze, Julian
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
    Heinemann, Nicolas
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
    Mühlemann, Barbara
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
    Schroeder, Simon
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
    Jones, Terry C.
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Centre for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, United Kingdom.
    Müller, Marcel A.
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
    Drosten, Christian
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
    Pich, Andreas
    Institute of Toxicology, Hannover Medical School, Core Facility Proteomics, Hannover, Germany.
    Thiel, Volker
    Institute of Virology and Immunology (IVI), University of Bern, Bern, Switzerland; Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
    Martin, Ulrich
    Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, REBIRTH—Center for Translational Regenerative Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany.
    Niemeyer, Daniela
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany; Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, The Hannover Medical School, The Helmholtz Centre for Infection Research, Hannover, Germany.
    Beule, Dieter
    Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany.
    Goffinet, Christine
    Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany; Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
    Pharmacological inhibition of bromodomain and extra-terminal proteins induces an NRF-2-mediated antiviral state that is subverted by SARS-CoV-2 infection2023In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 19, no 9, article id e1011657Article in journal (Refereed)
    Abstract [en]

    Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential prophylactics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-mediated antiviral activity and its susceptibility to viral subversion remain incompletely understood. Pretreatment of cells with iBETs inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. The antiviral activity manifested itself by reduced reporter expression of recombinant viruses, and reduced viral RNA quantities and infectious titers in the culture supernatant. While we confirmed JQ-1-mediated downregulation of expression of angiotensin-converting enzyme 2 (ACE2) and interferon-stimulated genes (ISGs), multi-omics analysis addressing the chromatin accessibility, transcriptome and proteome uncovered induction of an antiviral nuclear factor erythroid 2-related factor 2 (NRF-2)-mediated cytoprotective response as an additional mechanism through which JQ-1 inhibits SARS-CoV-2 replication. Pharmacological inhibition of NRF-2, and knockdown of NRF-2 and its target genes reduced JQ-1-mediated inhibition of SARS-CoV-2 replication. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variant, which exhibited resistance to JQ-1 and increased sensitivity to exogenously administered type I interferon (IFN-I), suggesting a minimised need for SARS-CoV-2 ORF6-mediated repression of IFN signalling in the presence of JQ-1. Importantly, JQ-1 exhibited a transient antiviral activity when administered prophylactically in human airway bronchial epithelial cells (hBAECs), which was gradually subverted by SARS-CoV-2, and no antiviral activity when administered therapeutically following an established infection. We propose that JQ-1 exerts pleiotropic effects that collectively induce an antiviral state in the host, which is ultimately nullified by SARS-CoV-2 infection, raising questions about the clinical suitability of the iBETs in the context of COVID-19.

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