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  • 1.
    Abidine, Yara
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Liu, Lifeng
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Wallén, Oskar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Trybala, Edward
    Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Olofsson, Sigvard
    Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Bergström, Tomas
    Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Cellular Chondroitin Sulfate and the Mucin-like Domain of Viral Glycoprotein C Promote Diffusion of Herpes Simplex Virus 1 While Heparan Sulfate Restricts Mobility2022In: Viruses, E-ISSN 1999-4915, Vol. 14, no 8, article id 1836Article in journal (Refereed)
    Abstract [en]

    The diffusion of viruses at the cell membrane is essential to reach a suitable entry site and initiate subsequent internalization. Although many viruses take advantage of glycosaminoglycans (GAG) to bind to the cell surface, little is known about the dynamics of the virus–GAG interactions. Here, single-particle tracking of the initial interaction of individual herpes simplex virus 1 (HSV-1) virions reveals a heterogeneous diffusive behavior, regulated by cell-surface GAGs with two main diffusion types: confined and normal free. This study reports that different GAGs can have competing influences in mediating diffusion on the cells used here: chondroitin sulfate (CS) enhances free diffusion but hinders virus attachment to cell surfaces, while heparan sulfate (HS) promotes virus confinement and increases entry efficiency. In addition, the role that the viral mucin-like domains (MLD) of the HSV-1 glycoprotein C plays in facilitating the diffusion of the virus and accelerating virus penetration into cells is demonstrated. Together, our results shed new light on the mechanisms of GAG-regulated virus diffusion at the cell surface for optimal internalization. These findings may be extendable to other GAG-binding viruses.

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  • 2. 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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  • 3.
    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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  • 4. Banse, Pia
    et al.
    Moeller, Rebecca
    Bruening, Janina
    Lasswitz, Lisa
    Kahl, Sina
    Khan, Abdul G
    Marcotrigiano, Joseph
    Pietschmann, Thomas
    Gerold, Gisa
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, 30625 Hannover, Germany.
    CD81 receptor regions outside the large extracellular loop determine hepatitis C virus entry into hepatoma cells2018In: Viruses, E-ISSN 1999-4915, Vol. 10, no 4, article id 207Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV) enters human hepatocytes using four essential entry factors, one of which is human CD81 (hCD81). The tetraspanin hCD81 contains a large extracellular loop (LEL), which interacts with the E2 glycoprotein of HCV. The role of the non-LEL regions of hCD81 (intracellular tails, four transmembrane domains, small extracellular loop and intracellular loop) is poorly understood. Here, we studied the contribution of these domains to HCV susceptibility of hepatoma cells by generating chimeras of related tetraspanins with the hCD81 LEL. Our results show that non-LEL regions in addition to the LEL determine susceptibility of cells to HCV. While closely related tetraspanins (X. tropicalis CD81 and D. rerio CD81) functionally complement hCD81 non-LEL regions, distantly related tetraspanins (C. elegans TSP9 amd D. melanogaster TSP96F) do not and tetraspanins with intermediate homology (hCD9) show an intermediate phenotype. Tetraspanin homology and susceptibility to HCV correlate positively. For some chimeras, infectivity correlates with surface expression. In contrast, the hCD9 chimera is fully surface expressed, binds HCV E2 glycoprotein but is impaired in HCV receptor function. We demonstrate that a cholesterol-coordinating glutamate residue in CD81, which hCD9 lacks, promotes HCV infection. This work highlights the hCD81 non-LEL regions as additional HCV susceptibility-determining factors.

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  • 5.
    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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  • 6.
    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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  • 7.
    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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  • 8.
    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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  • 9.
    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.

  • 10.
    Lindquist, Richard
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Benz, Caroline
    Department of Chemistry—BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Sereikaite, Vita
    Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark.
    Maassen, Lars
    Department of Chemistry—BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Laursen, Louise
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, Uppsala, Sweden.
    Jemth, Per
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, Uppsala, Sweden.
    Strømgaard, Kristian
    Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark.
    Ivarsson, Ylva
    Department of Chemistry—BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    A syntenin inhibitor blocks endosomal entry of SARS-CoV-2 and a panel of RNA viruses2022In: Viruses, E-ISSN 1999-4915, Vol. 14, no 10, article id 2202Article in journal (Refereed)
    Abstract [en]

    Viruses are dependent on host factors in order to efficiently establish an infection and replicate. Targeting the interactions of such host factors provides an attractive strategy to develop novel antivirals. Syntenin is a protein known to regulate the architecture of cellular membranes by its involvement in protein trafficking and has previously been shown to be important for human papilloma virus (HPV) infection. Here, we show that a highly potent and metabolically stable peptide inhibitor that binds to the PDZ1 domain of syntenin inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by blocking the endosomal entry of the virus. Furthermore, we found that the inhibitor also hampered chikungunya infection and strongly reduced flavivirus infection, which is completely dependent on receptor-mediated endocytosis for their entry. In conclusion, we have identified a novel broad spectrum antiviral inhibitor that efficiently targets a broad range of RNA viruses.

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  • 11.
    Lindqvist, Richard
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Upadhyay, Arunkumar S.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Tick-Borne Flaviviruses and the Type I Interferon Response2018In: Viruses, E-ISSN 1999-4915, Vol. 10, no 7, article id 340Article, review/survey (Refereed)
    Abstract [en]

    Flaviviruses are globally distributed pathogens causing millions of human infections every year. Flaviviruses are arthropod-borne viruses and are mainly transmitted by either ticks or mosquitoes. Mosquito-borne flaviviruses and their interactions with the innate immune response have been well-studied and reviewed extensively, thus this review will discuss tick-borne flaviviruses and their interactions with the host innate immune response.

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  • 12.
    Lipskij, Alexander
    et al.
    Theoretical Physics and Center of Interdisciplinary Nanostructure Science and Technology, Universität Kassel, Kassel, Germany.
    Arbeitman, Claudia
    Theoretical Physics and Center of Interdisciplinary Nanostructure Science and Technology, Universität Kassel, Kassel, Germany; CONICET Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; GIBIO-Universidad Tecnológica Nacional-Facultad Regional Buenos Aires, Buenos Aires, Argentina.
    Rojas, Pablo
    Theoretical Physics and Center of Interdisciplinary Nanostructure Science and Technology, Universität Kassel, Kassel, Germany.
    Ojeda-May, Pedro
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Garcia, Martin E.
    Theoretical Physics and Center of Interdisciplinary Nanostructure Science and Technology, Universität Kassel, Kassel, Germany.
    Dramatic differences between the structural susceptibility of the S1 pre- and S2 postfusion states of the SARS-CoV-2 spike protein to external electric fields revealed by molecular dynamics simulations2023In: Viruses, E-ISSN 1999-4915, Vol. 15, no 12, p. 2405-2419Article in journal (Refereed)
    Abstract [en]

    In its prefusion state, the SARS-CoV-2 spike protein (similarly to other class I viral fusion proteins) is metastable, which is considered to be an important feature for optimizing or regulating its functions. After the binding process of its S1 subunit (S1) with ACE2, the spike protein (S) undergoes a dramatic conformational change where S1 splits from the S2 subunit, which then penetrates the membrane of the host cell, promoting the fusion of the viral and cell membranes. This results in the infection of the host cell. In a previous work, we showed—using large-scale molecular dynamics simulations—that the application of external electric fields (EFs) induces drastic changes and damage in the receptor-binding domain (RBD) of the wild-type spike protein, as well of the Alpha, Beta, and Gamma variants, leaving a structure which cannot be recognized anymore by ACE2. In this work, we first extend the study to the Delta and Omicron variants and confirm the high sensitivity and extreme vulnerability of the RBD of the prefusion state of S to moderate EF (as weak as 104 V/m), but, more importantly, we also show that, in contrast, the S2 subunit of the postfusion state of the spike protein does not suffer structural damage even if electric field intensities four orders of magnitude higher are applied. These results provide a solid scientific basis to confirm the connection between the prefusion-state metastability of the SARS-CoV-2 spike protein and its susceptibility to be damaged by EF. After the virus docks to the ACE2 receptor, the stable and robust postfusion conformation develops, which exhibits a similar resistance to EF (damage threshold higher than 108 V/m) like most globular proteins.

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  • 13.
    Lwande, Olivia Wesula
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Thalin, Therese
    Department of Wildlife, Fish, and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden.
    de Jong, Johnny
    Swedish Biodiversity Centre (CBM), Department of Urban and Rural Development, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Sjödin, Andreas
    Division of CBRN Defence and Security, Swedish Defence Research Agency FOI, Umea, Sweden.
    Näslund, Jonas
    Division of CBRN Defence and Security, Swedish Defence Research Agency FOI, Umea, Sweden.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ecke, Frauke
    Department of Wildlife, Fish, and Environmental Studies, Swedish University of Agricultural Sciences, Umea, Sweden.
    Alphacoronavirus in a Daubenton’s Myotis Bat (Myotis daubentonii) in Sweden2022In: Viruses, E-ISSN 1999-4915, Vol. 14, no 3, article id 556Article in journal (Refereed)
    Abstract [en]

    The ongoing COVID-19 pandemic has stimulated a search for reservoirs and species potentially involved in back and forth transmission. Studies have postulated bats as one of the key reservoirs of coronaviruses (CoVs), and different CoVs have been detected in bats. So far, CoVs have not been found in bats in Sweden and we therefore tested whether they carry CoVs. In summer 2020, we sampled a total of 77 adult bats comprising 74 Myotis daubentonii, 2 Pipistrellus pygmaeus, and 1 M. mystacinus bats in southern Sweden. Blood, saliva and feces were sampled, processed and subjected to a virus next-generation sequencing target enrichment protocol. An Alphacoronavirus was detected and sequenced from feces of a M. daubentonii adult female bat. Phylogenetic analysis of the almost complete virus genome revealed a close relationship with Finnish and Danish strains. This was the first finding of a CoV in bats in Sweden, and bats may play a role in the transmission cycle of CoVs in Sweden. Focused and targeted surveillance of CoVs in bats is warranted, with consideration of potential conflicts between public health and nature conservation required as many bat species in Europe are threatened and protected.

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  • 14.
    Masika, Moses Muia
    et al.
    KAVI Institute of Clinical Research, University of Nairobi, POB 19676, Nairobi, Kenya; Department of Medical Microbiology, University of Nairobi, POB 19676, Nairobi, Kenya.
    Korhonen, Essi M.
    Department of Virology, University of Helsinki, Helsinki, Finland; Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.
    Smura, Teemu
    Department of Virology, University of Helsinki, Helsinki, Finland; HUS Diagnostic Center, HUSLAB, Virology and Immunology, Helsinki University Hospital, Helsinki, Finland.
    Uusitalo, Ruut
    Department of Virology, University of Helsinki, Helsinki, Finland; Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland; Department of Geosciences and Geography, University of Helsinki, Helsinki, Finland.
    Ogola, Joseph
    KAVI Institute of Clinical Research, University of Nairobi, POB 19676, Nairobi, Kenya; Department of Medical Microbiology, University of Nairobi, POB 19676, Nairobi, Kenya.
    Mwaengo, Dufton
    Department of Medical Microbiology, University of Nairobi, POB 19676, Nairobi, Kenya.
    Jääskeläinen, Anne J.
    Department of Virology, University of Helsinki, Helsinki, Finland; HUS Diagnostic Center, HUSLAB, Virology and Immunology, Helsinki University Hospital, Helsinki, Finland.
    Alburkat, Hussein
    Department of Virology, University of Helsinki, Helsinki, Finland.
    Yong-Dae, Gwon
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Anzala, Omu
    KAVI Institute of Clinical Research, University of Nairobi, POB 19676, Nairobi, Kenya; Department of Medical Microbiology, University of Nairobi, POB 19676, Nairobi, Kenya.
    Vapalahti, Olli
    Department of Virology, University of Helsinki, Helsinki, Finland; Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland; HUS Diagnostic Center, HUSLAB, Virology and Immunology, Helsinki University Hospital, Helsinki, Finland.
    Huhtamo, Eili
    Department of Virology, University of Helsinki, Helsinki, Finland; Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.
    Serological Evidence of Exposure to Onyong-Nyong and Chikungunya Viruses in Febrile Patients of Rural Taita-Taveta County and Urban Kibera Informal Settlement in Nairobi, Kenya2022In: Viruses, E-ISSN 1999-4915, Vol. 14, no 6, article id 1286Article in journal (Refereed)
    Abstract [en]

    Several alphaviruses, such as chikungunya (CHIKV) and Onyong-nyong (ONNV), are endemic in Kenya and often cause outbreaks in different parts of the country. We assessed the seroprevalence of alphaviruses in patients with acute febrile illness in two geographically distant areas in Kenya with no previous record of alphavirus outbreaks. Blood samples were collected from febrile patients in health facilities located in the rural Taita-Taveta County in 2016 and urban Kibera informal settlement in Nairobi in 2017 and tested for CHIKV IgG and IgM antibodies using an in-house immunofluorescence assay (IFA) and a commercial ELISA test, respectively. A subset of CHIKV IgG or IgM antibody-positive samples were further analyzed using plaque reduction neutralization tests (PRNT) for CHIKV, ONNV, and Sindbis virus. Out of 537 patients, 4 (0.7%) and 28 (5.2%) had alphavirus IgM and IgG antibodies, respectively, confirmed on PRNT. We show evidence of previous and current exposure to alphaviruses based on serological testing in areas with no recorded history of outbreaks.

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  • 15.
    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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  • 16.
    Nilsson, Emelie
    et al.
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM); Centre for Ecology and Evolution in Microbial Model Systems (EEMiS).
    Bayfield, Oliver W.
    York Structural Biology Laboratory, Department of Chemistry, University of York, York, UK.
    Lundin, Daniel
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM); Centre for Ecology and Evolution in Microbial Model Systems (EEMiS).
    Antson, Alfred A.
    atory, Department of Chemistry, University of York, York, UK.
    Holmfeldt, Karin
    Ecology and Evolution in Microbial Model Systems (EEMiS).
    Diversity and host interactions among virulent and temperate Baltic Sea Flavobacterium phages2020In: Viruses, E-ISSN 1999-4915, Vol. 12, no 2, article id 158Article in journal (Refereed)
    Abstract [en]

    Viruses in aquatic environments play a key role in microbial population dynamics and nutrient cycling. In particular, bacteria of the phylum Bacteriodetes are known to participate in recycling algal blooms. Studies of phage-host interactions involving this phylum are hence important to understand the processes shaping bacterial and viral communities in the ocean as well as nutrient cycling. In this study, we isolated and sequenced three strains of flavobacteria-LMO6, LMO9, LMO8-and 38 virulent phages infecting them. These phages represent 15 species, occupying three novel genera. Additionally, one temperate phage was induced from LMO6 and was found to be competent at infecting LMO9. Functions could be predicted for a limited number of phage genes, mainly representing roles in DNA replication and virus particle formation. No metabolic genes were detected. While the phages isolated on LMO8 could infect all three bacterial strains, the LMO6 and LMO9 phages could not infect LMO8. Of the phages isolated on LMO9, several showed a host-derived reduced efficiency of plating on LMO6, potentially due to differences in DNA methyltransferase genes. Overall, these phage-host systems contribute novel genetic information to our sequence databases and present valuable tools for the study of both virulent and temperate phages.

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  • 17.
    Persson, B. David
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Nord, Stefan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lindquist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Danskog, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Kohl, Alain
    MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
    Willison, Hugh J.
    Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    BAF45b is required for efficient zika virus infection of HAP1 cells2021In: Viruses, E-ISSN 1999-4915, Vol. 13, no 10, article id 2007Article in journal (Refereed)
    Abstract [en]

    The 2016 Zika virus (ZIKV) epidemic illustrates the impact of flaviviruses as emerging human pathogens. For unknown reasons, ZIKV replicates more efficiently in neural progenitor cells (NPCs) than in postmitotic neurons. Here, we identified host factors used by ZIKV using the NCI-60 library of cell lines and COMPARE analysis, and cross-analyzed this library with two other libraries of host factors with importance for ZIKV infection. We identified BAF45b, a subunit of the BAF (Brg1/Brm-associated factors) protein complexes that regulate differentiation of NPCs to post-mitotic neurons. ZIKV (and other flaviviruses) infected HAP1 cells deficient in expression of BAF45b and other BAF subunits less efficiently than wildtype (WT) HAP1 cells. We concluded that subunits of the BAF complex are important for infection of ZIKV and other flavivirus. Given their function in cell and tissue differentiation, such regulators may be important determinants of tropism and pathogenesis of arthropod-borne flaviviruses.

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  • 18.
    Pulkkinen, Lauri I. A.
    et al.
    Faculty of Biological and Environmental Sciences, Molecular and Integrative Bioscience Research Programme, University of Helsinki, Helsinki, Finland; Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Barrass, Sarah V.
    Faculty of Biological and Environmental Sciences, Molecular and Integrative Bioscience Research Programme, University of Helsinki, Helsinki, Finland; Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Domanska, Aušra
    Faculty of Biological and Environmental Sciences, Molecular and Integrative Bioscience Research Programme, University of Helsinki, Helsinki, Finland; Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Anastasina, Maria
    Faculty of Biological and Environmental Sciences, Molecular and Integrative Bioscience Research Programme, University of Helsinki, Helsinki, Finland; Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Butcher, Sarah J.
    Faculty of Biological and Environmental Sciences, Molecular and Integrative Bioscience Research Programme, University of Helsinki, Helsinki, Finland; Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Molecular Organisation of Tick-Borne Encephalitis Virus2022In: Viruses, E-ISSN 1999-4915, Vol. 14, no 4, article id 792Article in journal (Refereed)
    Abstract [en]

    Tick-borne encephalitis virus (TBEV) is a pathogenic, enveloped, positive-stranded RNA virus in the family Flaviviridae. Structural studies of flavivirus virions have primarily focused on mosquito-borne species, with only one cryo-electron microscopy (cryo-EM) structure of a tick-borne species published. Here, we present a 3.3 Å cryo-EM structure of the TBEV virion of the Kuutsalo-14 isolate, confirming the overall organisation of the virus. We observe conformational switching of the peripheral and transmembrane helices of M protein, which can explain the quasi-equivalent packing of the viral proteins and highlights their importance in stabilising membrane protein arrangement in the virion. The residues responsible for M protein interactions are highly conserved in TBEV but not in the structurally studied Hypr strain, nor in mosquito-borne flaviviruses. These interactions may compensate for the lower number of hydrogen bonds between E proteins in TBEV compared to the mosquito-borne flaviviruses. The structure reveals two lipids bound in the E protein which are important for virus assembly. The lipid pockets are comparable to those recently described in mosquito-borne Zika, Spondweni, Dengue, and Usutu viruses. Our results thus advance the understanding of tick-borne flavivirus architecture and virion-stabilising interactions.

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  • 19.
    Rajan, Anandi
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Sweden.
    Palm, Elin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Trulsson, Fredrik
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.
    Mundigl, Sarah
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Becker, Miriam
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). 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.
    Persson, David
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. National Veterinary Institute, SVA, Uppsala, Sweden.
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). 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.
    Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses2021In: Viruses, E-ISSN 1999-4915, Vol. 13, no 2, article id 298Article in journal (Refereed)
    Abstract [en]

    Human adenovirus (HAdV)-F40 and -F41 are leading causes of diarrhea and diarrhea-associated mortality in children under the age of five, but the mechanisms by which they infect host cells are poorly understood. HAdVs initiate infection through interactions between the knob domain of the fiber capsid protein and host cell receptors. Unlike most other HAdVs, HAdV-F40 and -F41 possess two different fiber proteins-a long fiber and a short fiber. Whereas the long fiber binds to the Coxsackievirus and adenovirus receptor (CAR), no binding partners have been identified for the short fiber. In this study, we identified heparan sulfate (HS) as an interaction partner for the short fiber of enteric HAdVs. We demonstrate that exposure to acidic pH, which mimics the environment of the stomach, inactivates the interaction of enteric adenovirus with CAR. However, the short fiber:HS interaction is resistant to and even enhanced by acidic pH, which allows attachment to host cells. Our results suggest a switch in receptor usage of enteric HAdVs after exposure to acidic pH and add to the understanding of the function of the short fibers. These results may also be useful for antiviral drug development and the utilization of enteric HAdVs for clinical applications such as vaccine development.

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  • 20.
    Trybala, Edward
    et al.
    Department of Infectious Diseases, Section for Clinical Virology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
    Peerboom, Nadia
    Department of Physics, Chalmers University of Technology, Göteborg, Sweden.
    Adamiak, Beata
    Department of Infectious Diseases, Section for Clinical Virology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
    Krzyzowska, Malgorzata
    Department of Infectious Diseases, Section for Clinical Virology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
    Liljeqvist, Jan-Åke
    Department of Infectious Diseases, Section for Clinical Virology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Bergström, Tomas
    Department of Infectious Diseases, Section for Clinical Virology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
    Herpes simplex virus type 2 mucin-like glycoprotein mgg promotes virus release from the surface of infected cells2021In: Viruses, E-ISSN 1999-4915, Vol. 13, no 5, article id 887Article in journal (Refereed)
    Abstract [en]

    The contribution of virus components to liberation of herpes simplex virus type 2 (HSV-2) progeny virions from the surface of infected cells is poorly understood. We report that the HSV-2 mutant deficient in the expression of a mucin-like membrane-associated glycoprotein G (mgG) exhibited defect in the release of progeny virions from infected cells manifested by ~2 orders of magnitude decreased amount of infectious virus in a culture medium as compared to native HSV-2. Electron microscopy revealed that the mgG deficient virions were produced in infected cells and present at the cell surface. These virions could be forcibly liberated to a nearly native HSV-2 level by the treatment of cells with glycosaminoglycan (GAG)-mimicking oligosaccharides. Comparative assessment of the interaction of mutant and native virions with surface-immobilized chondroitin sulfate GAG chains revealed that while the mutant virions associated with GAGs ~fourfold more extensively, the lateral mobility of bound virions was much poorer than that of native virions. These data indicate that the mgG of HSV-2 balances the virus interaction with GAG chains, a feature critical to prevent trapping of the progeny virions at the surface of infected cells.

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  • 21.
    Yong-Dae, Gwon
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Mahani, Seyed Alireza Nematollahi
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Rift valley fever virus propagates in human villous trophoblast cell lines and induces cytokine mrna responses known to provoke miscarriage2021In: Viruses, E-ISSN 1999-4915, Vol. 13, no 11, article id 2265Article in journal (Refereed)
    Abstract [en]

    The mosquito-borne Rift Valley fever (RVF) is a prioritised disease that has been listed by the World Health Organization for urgent research and development of counteraction. Rift Valley fever virus (RVFV) can cause a cytopathogenic effect in the infected cell and induce hyperimmune responses that contribute to pathogenesis. In livestock, the consequences of RVFV infection vary from mild symptoms to abortion. In humans, 1–3% of patients with RVFV infection develop severe disease, manifested as, for example, haemorrhagic fever, encephalitis or blindness. RVFV infection has also been associated with miscarriage in humans. During pregnancy, there should be a balance between pro-inflammatory and anti-inflammatory mediators to create a protective environment for the placenta and foetus. Many viruses are capable of penetrating that protective environment and infecting the foetal–maternal unit, possibly via the trophoblasts in the placenta, with potentially severe consequences. Whether it is the viral infection per se, the immune response, or both that contribute to the pathogenesis of miscarriage remains unknown. To investigate how RVFV could contribute to pathogenesis during pregnancy, we infected two human trophoblast cell lines, A3 and Jar, representing normal and transformed human villous trophoblasts, respectively. They were infected with two RVFV variants (wild-type RVFV and RVFV with a deleted NSs protein), and the infection kinetics and 15 different cytokines were analysed. The trophoblast cell lines were infected by both RVFV variants and infection caused upregulation of messenger RNA (mRNA) expression for interferon (IFN) types I–III and inflammatory cytokines, combined with cell linespecific mRNA expression of transforming growth factor (TGF)-β1 and interleukin (IL)-10. When comparing the two RVFV variants, we found that infection with RVFV lacking NSs function caused a hyper-IFN response and inflammatory response, while the wild-type RVFV suppressed the IFN I and inflammatory response. The induction of certain cytokines by RVFV infection could potentially lead to teratogenic effects that disrupt foetal and placental developmental pathways, leading to birth defects and other pregnancy complications, such as miscarriage.

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  • 22.
    Yong-Dae, Kwon
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Zusinaite, Eva
    Merits, Andres
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    N-glycosylation in the Pre-Membrane Protein Is Essential for the Zika Virus Life Cycle2020In: Viruses, E-ISSN 1999-4915, Vol. 12, no 9, article id 925Article in journal (Refereed)
    Abstract [en]

    Asparagine (N)-linked protein glycosylation plays an important role in protein synthesis and modification. Two Zika virus (ZIKV) structural proteins, the pre-membrane (prM) and envelope (E) protein areN-glycosylated. The prM protein of all ZIKV strains contains a singleN-linked glycosylation site, while not all strains contain an N-linked site in the E protein. Our aim was to examine the impact of prM and E N-linked glycosylation on ZIKV infectivity and cell trafficking. Using a ZIKV infectious clone, we found that when theN-glycan sites were removed, the prM- and the prM/E-double mutants did not produce an infectious virus in the supernatant. Further, by using ZIKV prME constructs, we found thatN-glycosylation was necessary for effective secretion of ZIKV virions. The absence of theN-glycan on prM or E caused protein aggregation in the rough endoplasmatic reticulum (ER) compartment. The aggregation was more pronounced for the prM-mutation, and the mutant virus lost the ER-Golgi intermediate compartment (ERGIC) localization. In addition, lack of theN-glycan on prM induced nuclear translocation of CCAAT-enhancer-binding protein homologous protein (CHOP), an ER stress marker. To conclude, we show that the prMN-glycan is essential for the ZIKV infectious cycle, and plays an important role in viral protein trafficking, protein folding, and virion assembly.

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  • 23. Zapatero-Belinchon, Francisco J.
    et al.
    Dietzel, Erik
    Dolnik, Olga
    Doehner, Katinka
    Costa, Rui
    Hertel, Barbara
    Veselkova, Barbora
    Kirui, Jared
    Klintworth, Anneke
    Manns, Michael P.
    Poehlmann, Stefan
    Pietschmann, Thomas
    Krey, Thomas
    Ciesek, Sandra
    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, Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany.
    Sodeik, Beate
    Becker, Stephan
    von Hahn, Thomas
    Characterization of the Filovirus-Resistant Cell Line SH-SY5Y Reveals Redundant Role of Cell Surface Entry Factors2019In: Viruses, E-ISSN 1999-4915, Vol. 11, no 3, article id 275Article in journal (Refereed)
    Abstract [en]

    Filoviruses infect a wide range of cell types with the exception of lymphocytes. The intracellular proteins cathepsin B and L, two-pore channel 1 and 2, and bona fide receptor Niemann-Pick Disease C1 (NPC1) are essential for the endosomal phase of cell entry. However, earlier steps of filoviral infection remain poorly characterized. Numerous plasma membrane proteins have been implicated in attachment but it is still unclear which ones are sufficient for productive entry. To define a minimal set of host factors required for filoviral glycoprotein-driven cell entry, we screened twelve cell lines and identified the nonlymphocytic cell line SH-SY5Y to be specifically resistant to filovirus infection. Heterokaryons of SH-SY5Y cells fused to susceptible cells were susceptible to filoviruses, indicating that SH-SY5Y cells do not express a restriction factor but lack an enabling factor critical for filovirus entry. However, all tested cell lines expressed functional intracellular factors. Global gene expression profiling of known cell surface entry factors and protein expression levels of analyzed attachment factors did not reveal any correlation between susceptibility and expression of a specific host factor. Using binding assays with recombinant filovirus glycoprotein, we identified cell attachment as the step impaired in filovirus entry in SH-SY5Y cells. Individual overexpression of attachment factors T-cell immunoglobulin and mucin domain 1 (TIM-1), Axl, Mer, or dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) rendered SH-SY5Y cells susceptible to filovirus glycoprotein-driven transduction. Our study reveals that a lack of attachment factors limits filovirus entry and provides direct experimental support for a model of filoviral cell attachment where host factor usage at the cell surface is highly promiscuous.

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