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  • 1.
    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.

  • 2.
    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, ISSN 1999-4915, 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.

  • 3.
    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, ISSN 1999-4915, 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.

  • 4.
    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, ISSN 1999-4915, 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.

  • 5.
    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, 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

  • 6. 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)
  • 7.
    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.

  • 8.
    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. 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.

  • 9. Peerboom, Nadia
    et al.
    Schmidt, Eneas
    Trybala, Edward
    Block, Stephan
    Bergström, Tomas
    Pace, Hudson P.
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Cell Membrane Derived Platform To Study Virus Binding Kinetics and Diffusion with Single Particle Sensitivity2018In: Acs Infectious Diseases, ISSN 2373-8227, Vol. 4, no 6, p. 944-953Article in journal (Refereed)
    Abstract [en]

    Discovery and development of new antiviral therapies essentially rely on two key factors: an in-depth understanding of the mechanisms involved in viral infection and the development of fast and versatile drug screening platforms. To meet those demands, we present a biosensing platform to probe virus-cell membrane interactions on a single particle level. Our method is based on the formation of supported lipid bilayers from cell membrane material. Using total internal reflection fluorescence microscopy, we report the contribution of viral and cellular components to the interaction kinetics of herpes simplex virus type 1 with the cell membrane. Deletion of glycoprotein C (gC), the main viral attachment glycoprotein, or deletion of heparan sulfate, an attachment factor on the cell membrane, leads to an overall decrease in association of virions to the membrane and faster dissociation from the membrane. In addition to this, we perform binding inhibition studies using the antiviral compound heparin to estimate its IC50 value. Finally, single particle tracking is used to characterize the diffusive behavior of the virus particles on the supported lipid bilayers. Altogether, our results promote this platform as a complement to existing bioanalytical assays, being at the interface between simplified artificial membrane models and live cell experiments.

  • 10.
    Rodrigues, Raquel
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Danskog, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Överby, Anna K.
    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.
    Characterizing the cellular attachment receptor for Langat virus2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 6, article id e0217359Article in journal (Refereed)
    Abstract [en]

    Tick-borne encephalitis infections have increased the last 30 years. The mortality associated to this viral infection is 0.5 to 30% with a risk of permanent neurological sequelae, however, no therapeutic is currently available. The first steps of virus-cell interaction, such as attachment and entry, are of importance to understand pathogenesis and tropism. Several molecules have been shown to interact with tick-borne encephalitis virus (TBEV) at the plasma membrane surface, yet, no studies have proven that these are specific entry receptors. In this study, we set out to characterize the cellular attachment receptor(s) for TBEV using the naturally attenuated member of the TBEV complex, Langat virus (LGTV), as a model. Inhibiting or cleaving different molecules from the surface of A549 cells, combined with inhibition assays using peptide extracts from high LGTV binding cells, revealed that LGTV attachment to host cells is dependent on plasma membrane proteins, but not on glycans or glycolipids, and suggested that LGTV might use different cellular attachment factors on different cell types. Based on this, we developed a transcriptomic approach to generate a list of candidate attachment and entry receptors. Our findings shed light on the first step of the flavivirus life-cycle and provide candidate receptors that might serve as a starting point for future functional studies to identify the specific attachment and/or entry receptor for LGTV and TBEV.

  • 11.
    Rusanganwa, Vincent
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. University of Rwanda, College of Medicine and Health Sciences, Kigali, Rwanda; Ministry of Health, Kigali, Rwanda.
    Gahutu, Jean Bosco
    University of Rwanda, College of Medicine and Health Sciences, Kigali, Rwanda.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Hurtig, Anna-Karin
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Clinical Referral Laboratory Personnel’s Perception of Challenges and Strategies for Sustaining the Laboratory Quality Management System: A Qualitative Study in Rwanda2019In: American Journal of Clinical Pathology, ISSN 0002-9173, E-ISSN 1943-7722Article in journal (Refereed)
    Abstract [en]

    Objectives: To explore challenges explaining the decrease in quality performance and suggest strategies to improve and sustain laboratory quality services.

    Methods: Twenty key informants’ interviews from laboratory personnel were conducted in five laboratories. Four had previously shown a decrease in quality performance. Interviews were transcribed verbatim and analyzed using inductive thematic analysis.

    Results: Two themes emerged: (1) insufficient coordination and follow-up system towards accreditation, where lack of coordination, follow-up, and audits explained the decrease in performance; (2) inadequate resource optimization, where insufficient knowledge in Laboratory Quality Management System (LQMS), ownership by laboratory workforce, and insufficient stakeholders’ communication contributed to low-quality performance.

    Conclusions: The coordination, follow-up, and assessments of LQMS, in conjunction with training of laboratory workforce, would establish an institutional culture of continuous quality improvement (CQI) towards accreditation and sustainment of quality health care. To achieve CQI culture, routine gap checking and planning for improvement using a system approach is required.

  • 12.
    Rusanganwa, Vincent
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Gahutu, Jean Bosco
    Nzabahimana, Innocent
    Ngendakabaniga, Jean Marie Vianney
    Hurtig, Anna-Karin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Clinical Referral Laboratories in Rwanda: The Status of Quality Improvement After 7 Years of the SLMTA Program2018In: American Journal of Clinical Pathology, ISSN 0002-9173, E-ISSN 1943-7722, Vol. 150, no 3, p. 240-245Article in journal (Refereed)
    Abstract [en]

    Objectives: We investigated the quality system performance in Rwandan referral laboratories to determine their progress toward accreditation.

    Methods: We conducted audits across five laboratories in 2017, using the Stepwise Laboratory Quality Improvement Process Towards Accreditation checklist. Laboratories were scored based on the World Health Organization grading scale (0-5 stars scale) and compared with earlier audits.

    Results: Between 2012 and 2017, only one laboratory progressed (from four to five stars). Four of the five laboratories decreased to one (three laboratories) and zero (one laboratory) stars from four and three stars. Management reviews, evaluation, audits, documents, records, and identification of nonconformities showed a low performance.

    Conclusions: Four of five laboratories are not moving toward accreditation. However, this target is still achievable by energizing responsibilities of stakeholders and monitoring and evaluation. This would be possible because of the ability that laboratories showed in earlier audits, coupled with existing health policy that enables sustainable quality health care in Rwanda.

  • 13. Ruzek, Daniel
    et al.
    Zupanc, Tatjana Avsic
    Borde, Johannes
    Chrdle, Ales
    Eyer, Ludek
    Karganova, Galina
    Kholodilov, Ivan
    Knap, Natasa
    Kozlovskaya, Liubov
    Matveev, Andrey
    Miller, Andrew D.
    Osolodkin, Dmitry I.
    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.
    Tikunova, Nina
    Tkachev, Sergey
    Zajkowska, Joanna
    Tick-borne encephalitis in Europe and Russia: review of pathogenesis, clinical features, therapy, and vaccines2019In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 164, p. 23-51Article, review/survey (Refereed)
    Abstract [en]

    Tick-borne encephalitis (TBE) is an illness caused by tick-borne encephalitis virus (TBEV) infection which is often limited to a febrile illness, but may lead to very aggressive downstream neurological manifestations. The disease is prevalent in forested areas of Europe and northeastern Asia, and is typically caused by infection involving one of three TBEV subtypes, namely the European (TBEV-Eu), the Siberian (TBEV-Sib), or the Far Eastern (TBEV-FE) subtypes. In addition to the three main TBEV subtypes, two other subtypes; i.e., the Baikalian (TBEV-Bkl) and the Himalayan subtype (TBEV-Him), have been described recently. In Europe, TBEV-Eu infection usually results in only mild TBE associated with a mortality rate of < 2%. TBEV-Sib infection also results in a generally mild TBE associated with a non-paralytic febrile form of encephalitis, although there is a tendency towards persistent TBE caused by chronic viral infection. TBE-FE infection is considered to induce the most severe forms of TBE. Importantly though, viral subtype is not the sole determinant of TBE severity; both mild and severe cases of TBE are in fact associated with infection by any of the subtypes. In keeping with this observation, the overall TBE mortality rate in Russia is similar to 2%, in spite of the fact that TBEV-Sib and TBEV-FE subtypes appear to be inducers of more severe TBE than TBEV-Eu. On the other hand, TBEV-Sib and TBEV-FE subtype infections in Russia are associated with essentially unique forms of TBE rarely seen elsewhere if at all, such as the hemorrhagic and chronic (progressive) forms of the disease. For post-exposure prophylaxis and TBE treatment in Russia and Kazakhstan, a specific anti-TBEV immunoglobulin is currently used with well-documented efficacy, but the use of specific TBEV immunoglobulins has been discontinued in Europe due to concerns regarding antibody-enhanced disease in naive individuals. Therefore, new treatments are essential. This review summarizes available data on the pathogenesis and clinical features of TBE, plus different vaccine preparations available in Europe and Russia. In addition, new treatment possibilities, including small molecule drugs and experimental immunotherapies are reviewed. The authors caution that their descriptions of approved or experimental therapies should not be considered to be recommendations for patient care.

  • 14. 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, ISSN 1999-4915, 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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