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  • 1.
    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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  • 2.
    Jonsson, Mari
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lenman, Annasara E
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nyberg, Cecilia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Abdullahi, Mohamed
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Coagulation factors IX and X enhance binding and infection of adenovirus types 5 and 31 in human epithelial cells2009In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 83, no 8, p. 3816-3825Article in journal (Refereed)
    Abstract [en]

    Most adenoviruses bind directly to the coxsackie and adenovirus receptor (CAR) on target cells in vitro, but recent research has shown that adenoviruses can also use soluble components in body fluids for indirect binding to target cells. These mechanisms have been identified upon addressing the questions of how to de- and retarget adenovirus-based vectors for human gene and cancer therapy, but the newly identified mechanisms also suggest that the role of body fluids and their components may also be of importance for natural, primary infections. Here we demonstrate that plasma, saliva, and tear fluid promote binding and infection of adenovirus type 5 (Ad5) in respiratory and ocular epithelial cells, which corresponds to the natural tropism of most adenoviruses, and that plasma promotes infection by Ad31. By using a set of binding and infection experiments, we also found that Ad5 and Ad31 require coagulation factors IX (FIX) or X (FX) or just FIX, respectively, for efficient binding and infection. The concentrations of these factors that were required for maximum binding were 1/100th of the physiological concentrations. Preincubation of virions with heparin or pretreatment of cells with heparinase I indicated that the role of cell surface heparan sulfate during FIX- and FX-mediated adenovirus binding and infection is mechanistically serotype specific. We conclude that the use of coagulation factors by adenoviruses may be of importance not only for the liver tropism seen when administering adenovirus vectors to the circulation but also during primary infections by wild-type viruses of their natural target cell types.

  • 3. Kirui, Jared
    et al.
    Abidine, Yara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Centre for Experimental and Clinical Infection Research, TWINCORE, Institute for Experimental Virology, a Joint Venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Islam, Md. Koushikul
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Yong-Dae, Gwon
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lasswitz, Lisa
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    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).
    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. Centre for Experimental and Clinical Infection Research, TWINCORE, Institute for Experimental Virology, a Joint Venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 7, article id 1828Article in journal (Refereed)
    Abstract [en]

    Chikungunya virus (CHIKV) is a re-emerging, mosquito-transmitted, enveloped positive stranded RNA virus. Chikungunya fever is characterized by acute and chronic debilitating arthritis. Although multiple host factors have been shown to enhance CHIKV infection, the molecular mechanisms of cell entry and entry factors remain poorly understood. The phosphatidylserine-dependent receptors, T-cell immunoglobulin and mucin domain 1 (TIM-1) and Axl receptor tyrosine kinase (Axl), are transmembrane proteins that can serve as entry factors for enveloped viruses. Previous studies used pseudoviruses to delineate the role of TIM-1 and Axl in CHIKV entry. Conversely, here, we use the authentic CHIKV and cells ectopically expressing TIM-1 or Axl and demonstrate a role for TIM-1 in CHIKV infection. To further characterize TIM-1-dependent CHIKV infection, we generated cells expressing domain mutants of TIM-1. We show that point mutations in the phosphatidylserine binding site of TIM-1 lead to reduced cell binding, entry, and infection of CHIKV. Ectopic expression of TIM-1 renders immortalized keratinocytes permissive to CHIKV, whereas silencing of endogenously expressed TIM-1 in human hepatoma cells reduces CHIKV infection. Altogether, our findings indicate that, unlike Axl, TIM-1 readily promotes the productive entry of authentic CHIKV into target cells.

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  • 4.
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Adenovirus-host interactions: implications for tropism and therapy2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human adenoviruses (HAdVs) are common viruses often associated withgastrointestinal, ocular and respiratory infections. They can infect a widevariety of cells, both dividing and non-dividing. HAdVs attach to and infecttarget cells through interactions with cellular receptors. It has also beenshown that HAdVs can use soluble host components in body fluids forindirect binding to target cells, a feature that enables the usage of new typesof receptors resulting in a more efficient HAdV infection. We thereforeevaluated the influence of soluble components from four different bodyfluids on HAdV infection of epithelial cells, representing the respiratory andocular tropism of most HAdVs. We found that plasma, saliva, and tear fluidpromote binding and infection of HAdV-5 (species C) and that plasmapromotes infection of HAdV-31 (species A). Further binding and infectionexperiments identified coagulation factor IX (FIX) and X (FX) as thecomponents of plasma responsible for increase of HAdV-5 infection whileFIX alone mediates increase of HAdV-31 infection. We found that as little as1% of the physiological concentration of these factors is required to facilitatemaximum binding.

    The effect of coagulation factors on HAdV infection was thereafterextended to include all species A HAdVs: HAdV-12, -18 and -31. Species AHAdVs normally cause infections involving the airways and/or the intestine.These infections are often mild but species A HAdVs in general, and HAdV-31 in particular, have been shown to cause severe and life-threateninginfections in immunocompromised patients. We show here that FIXefficiently increase HAdV-18 and -31 (but not HAdV-12) binding andinfection of human epithelial cells, representing the respiratory andgastrointestinal tropism. FIX was shown to interact with the hexon proteinof HAdV-31 and surface plasmon resonance analysis revealed that theHAdV-31:FIX interaction is slightly stronger than that of the HAdV-5:FIX/FX interactions, but more interestingly, the half-lives of theseinteractions are profoundly different. By performing binding and infectionexperiments using cells expressing specific glycosaminoglycans (GAGs) and ivGAG-cleaving enzymes we found that the HAdV-31:FIX and HAdV-5:FIX/FX complexes bind to heparan sulfate-containing GAGs on targetcells, but we could also see a difference in GAG dependence and specificitybetween these complexes.We conclude that the use of coagulation factors might be of moreimportance than previously recognized and that this may affect not only theliver tropism seen when administering adenovirus vectors into thecirculation but also regulate primary infections by wild-type viruses of theirnatural target cells. We also believe that our findings may contribute tobetter design of HAdV-based vectors for gene and cancer therapy and thatthe interaction between the HAdV-31 hexon and FIX may serve as a targetfor antiviral treatment.

    HAdV vectors are mainly based on HAdV-5 and several problems haverecently become evident when using these vectors. Major challenges withHAdV-5 based vectors include pre-existing neutralizing antibodies, pooraccess to the receptor CAR (coxsackie and adenovirus receptor), and offtarget effects to the liver due to interactions with coagulation factors. Theneed for new HAdV vectors devoid of these problems is evident.HAdV-52 is one of only three HAdVs that are equipped with two differentfiber proteins, one long and one short. We show here, by means of bindingand infection experiments, that HAdV-52 can use CAR as a cellular receptor,but that most of the binding is dependent on sialic acid-containingglycoproteins. Flow cytometry, ELISA and surface plasmon resonanceanalyses revealed that the terminal knob domain of the long fiber (52LFK)binds to CAR, and the knob domain of the short fiber (52SFK) binds tosialylated glycoproteins. X-ray crystallographic analysis of 52SFK in complexwith sialic acid revealed a new sialic acid binding site compared to otherknown adenovirus:glycan interactions. Moreover, glycan array analysisidentified α2,8-linked oligosialic acid, mimicking the naturally occurringpolysialic acid (PSia), as a potential sialic acid-containing glycan receptor for52SFK. ELISA and surface plasmon resonance confirmed the ability of52SFK to interact with PSia. Flow cytometry analysis also showed a fivefold vincrease in binding of 52SFK to PSia-expressing cells compared to controlcells. X-ray crystallographic analysis of 52SFK in complex with oligo-PSiarevealed engagement at the non-reducing end of oligo-PSia to the canonicalsialic acid-binding site, but also suggested the presence of a 'steering rim'consisting of positively charged amino acids contributing to the contact bylong-range electrostatic interactions.

    PSia is nearly absent on cells in healthy adults but can be expressed inhigh amounts on several types of cancers including: glioma, neuroblastomaand lung cancer. We show here that the short fiber of HAdV-52 bindsspecifically to PSia. Taking into account that HAdV-52 has a supposedly lowseroprevalence and is incapable of interacting with coagulation factors webelieve that HAdV-52 based vectors can be useful for treatment of cancertypes with elevated PSia expression.

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  • 5. Lenman, Annasara
    et al.
    Liaci, A. Manuel
    Frängsmyr, Lars
    Liu, Yan
    Blaum, Bärbel S.
    Podgorski, Iva I.
    Harrach, Balázs
    Benkő, Mária
    Feizi, Ten
    Stehle, Thilo
    Arnberg, Niklas
    Human adenovirus 52 short fiber binds to polysialic acidManuscript (preprint) (Other academic)
  • 6.
    Lenman, Annasara
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Liaci, A. Manuel
    Liu, Yan
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Frank, Martin
    Blaum, Bärbel S.
    Chai, Wengang
    Podgorski, Iva I.
    Harrach, Balázs
    Benko, Mária
    Feizi, Ten
    Stehle, Thilo
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Polysialic acid is a cellular receptor for human adenovirus 522018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 18, p. E4264-E4273Article in journal (Refereed)
    Abstract [en]

    Human adenovirus 52 (HAdV-52) is one of only three known HAdVs equipped with both a long and a short fiber protein. While the long fiber binds to the coxsackie and adenovirus receptor, the function of the short fiber in the virus life cycle is poorly understood. Here, we show, by glycan microarray analysis and cellular studies, that the short fiber knob (SFK) of HAdV-52 recognizes long chains of α-2,8-linked polysialic acid (polySia), a large posttranslational modification of selected carrier proteins, and that HAdV-52 can use polySia as a receptor on target cells. X-ray crystallography, NMR, molecular dynamics simulation, and structure-guided mutagenesis of the SFK reveal that the nonreducing, terminal sialic acid of polySia engages the protein with direct contacts, and that specificity for polySia is achieved through subtle, transient electrostatic interactions with additional sialic acid residues. In this study, we present a previously unrecognized role for polySia as a cellular receptor for a human viral pathogen. Our detailed analysis of the determinants of specificity for this interaction has general implications for protein-carbohydrate interactions, particularly concerning highly charged glycan structures, and provides interesting dimensions on the biology and evolution of members of Human mastadenovirus G.

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  • 7.
    Lenman, Annasara
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Liaci, A. Manuel
    Liu, Yan
    Årdahl, Carin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Rajan, Anandi
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bradford, Will
    Kaeshammer, Lisa
    Jones, Morris S.
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Feizi, Ten
    Stehle, Thilo
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Human Adenovirus 52 Uses Sialic Acid-containing Glycoproteins and the Coxsackie and Adenovirus Receptor for Binding to Target Cells2015In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, no 2, article id e1004657Article in journal (Refereed)
    Abstract [en]

    Most adenoviruses attach to host cells by means of the protruding fiber protein that binds to host cells via the coxsackievirus and adenovirus receptor (CAR) protein. Human adenovirus type 52 (HAdV-52) is one of only three gastroenteritis-causing HAdVs that are equipped with two different fiber proteins, one long and one short. Here we show, by means of virion-cell binding and infection experiments, that HAdV-52 can also attach to host cells via CAR, but most of the binding depends on sialylated glycoproteins. Glycan microarray, flow cytometry, surface plasmon resonance and ELISA analyses reveal that the terminal knob domain of the long fiber (52LFK) binds to CAR, and the knob domain of the short fiber (52SFK) binds to sialylated glycoproteins. X-ray crystallographic analysis of 52SFK in complex with 2-O-methylated sialic acid combined with functional studies of knob mutants revealed a new sialic acid binding site compared to other, known adenovirus: glycan interactions. Our findings shed light on adenovirus biology and may help to improve targeting of adenovirus-based vectors for gene therapy.

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  • 8.
    Lenman, Annasara
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mueller, Steffen
    Nygren, Mari I
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Stehle, Thilo
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Coagulation factor IX mediates serotype-specific binding of species A adenoviruses to host cells2011In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 85, no 24, p. 13420-13431Article in journal (Refereed)
    Abstract [en]

    Human species A adenoviruses (HAdVs) comprise three serotypes: HAdV-12, -18, and -31. These viruses are common pathogens and cause systemic infections that usually involve the airways and/or intestine. In immunocompromised individuals, species A adenoviruses in general, and HAdV-31 in particular, cause life-threatening infections. By combining binding and infection experiments, we demonstrate that coagulation factor IX (FIX) efficiently enhances binding and infection by HAdV-18 and HAdV-31, but not by HAdV-12, in epithelial cells originating from the airways or intestine. This is markedly different from the mechanism for HAdV-5 and other human adenoviruses, which utilize coagulation factor X (FX) for infection of host cells. Surface plasmon resonance experiments revealed that the affinity of the HAdV-31 hexon-FIX interaction is higher than that of the HAdV-5 hexon-FX interaction and that the half-lives of these interactions are profoundly different. Moreover, both HAdV-31-FIX and HAdV-5-FX complexes bind to heparan sulfate-containing glycosaminoglycans (GAGs) on target cells, but binding studies utilizing cells expressing specific GAGs and GAG-cleaving enzymes revealed differences in GAG dependence and specificity between these two complexes. These findings add to our understanding of the intricate infection pathways used by human adenoviruses, and they may contribute to better design of HAdV-based vectors for gene and cancer therapy. Furthermore, the interaction between the HAdV-31 hexon and FIX may also serve as a target for antiviral treatment.

  • 9.
    Lindquist, Richard
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Weber, Elvira
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Asghar, Naveed
    School of Medical Sciences, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Schreier, Sarah
    Institute of Medical Microbiology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Johansson, Magnus
    School of Medical Sciences, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Dobler, Gerhard
    Bundeswehr Institute of Microbiology, Munich, Germany.
    Bestehorn, Malena
    Bundeswehr Institute of Microbiology, Munich, Germany; Parasitology Unit, University of Hohenheim, D-, Stuttgart, Germany.
    Kröger, Andrea
    Institute of Medical Microbiology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    The envelope protein of tick-borne encephalitis virus influences neuron entry, pathogenicity, and vaccine protection2020In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 17, no 1, article id 284Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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  • 10. Palor, Machaela
    et al.
    Stejskal, Lenka
    Mandal, Piya
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Alberione, Maria Pia
    Kirui, Jared
    Moeller, Rebecca
    Ebner, Stefan
    Meissner, Felix
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Shepherd, Adrian J.
    Grove, Joe
    Cholesterol sensing by CD81 is important for hepatitis C virus entry2020In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 295, no 50, p. 16931-16948Article in journal (Refereed)
    Abstract [en]

    CD81 plays a role in a variety of physiological and pathological processes. Recent structural analysis of CD81 indicates that it contains an intramembrane cholesterol-binding pocket and that interaction with cholesterol may regulate a conformational switch in the extracellular domain of CD81. Therefore, CD81 possesses a potential cholesterol sensing mechanism; however, its relevance for protein function is thus far unknown. In this study we investigate CD81 cholesterol sensing in the context of its activity as a receptor for hepatitis C virus. Structure-led mutagenesis of the cholesterol-binding pocket reduced CD81-cholesterol association, but had disparate effects on HCV, both reducing and enhancing CD81 receptor activity. We reasoned that this could be explained by alterations in the consequences of cholesterol binding. To investigate this further we performed molecular dynamic simulations of CD81 with and without cholesterol; this identified an allosteric mechanism by which cholesterol binding regulates the conformation of CD81. To test this, we designed further mutations to force CD81 into either the open (cholesterol unbound) or closed (cholesterol bound) conformation. The open mutant of CD81 exhibited reduced receptor activity whereas the closed mutant was enhanced. These data are consistent with cholesterol switching CD81 between a receptor active and inactive state. CD81 interactome analysis also suggests that conformational switching may modulate the assembly of CD81-partner networks. This work furthers our understanding of the molecular mechanism of CD81 cholesterol sensing, how this relates to HCV entry and CD81's function as a molecular scaffold; these insights are relevant to CD81's varied roles in health and disease.

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  • 11.
    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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  • 12.
    Persson, David
    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.
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Schmid, Markus
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Plückthun, Andreas
    Jenssen, Håvard
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Lactoferrin-Hexon Interactions Mediate CAR-Independent Adenovirus Infection of Human Respiratory Cells2020In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 94, no 14, article id e00542-20Article in journal (Refereed)
    Abstract [en]

    Virus entry into host cells is a complex process that is largely regulated by access to specific cellular receptors. Human adenoviruses (HAdVs) and many other viruses use cell adhesion molecules such as the coxsackievirus and adenovirus receptor (CAR) for attachment to and entry into target cells. These molecules are rarely expressed on the apical side of polarized epithelial cells, which raises the question of how adenoviruses—and other viruses that engage cell adhesion molecules—enter polarized cells from the apical side to initiate infection. We have previously shown that species C HAdVs utilize lactoferrin—a common innate immune component secreted to respiratory mucosa—for infection via unknown mechanisms. Using a series of biochemical, cellular, and molecular biology approaches, we mapped this effect to the proteolytically cleavable, positively charged, N-terminal 49 residues of human lactoferrin (hLF) known as human lactoferricin (hLfcin). Lactoferricin (Lfcin) binds to the hexon protein on the viral capsid and anchors the virus to an unknown receptor structure of target cells, resulting in infection. These findings suggest that HAdVs use distinct cell entry mechanisms at different stages of infection. To initiate infection, entry is likely to occur at the apical side of polarized epithelial cells, largely by means of hLF and hLfcin bridging HAdV capsids via hexons to as-yet-unknown receptors; when infection is established, progeny virions released from the basolateral side enter neighboring cells by means of hLF/hLfcin and CAR in parallel.

    IMPORTANCE: Many viruses enter target cells using cell adhesion molecules as receptors. Paradoxically, these molecules are abundant on the lateral and basolateral side of intact, polarized, epithelial target cells, but absent on the apical side that must be penetrated by incoming viruses to initiate infection. Our study provides a model whereby viruses use different mechanisms to infect polarized epithelial cells depending on which side of the cell—apical or lateral/basolateral—is attacked. This study may also be useful to understand the biology of other viruses that use cell adhesion molecules as receptors.

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  • 13.
    Rafie, Karim
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Fuchs, J.
    Rajan, Anandi
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    The structure of enteric human adenovirus 41: A leading cause of diarrhea in children2021In: Science Advances, E-ISSN 2375-2548, Vol. 7, no 2, article id eabe0974Article in journal (Refereed)
    Abstract [en]

    Human adenovirus (HAdV) types F40 and F41 are a prominent cause of diarrhea and diarrhea-associated mortality in young children worldwide. These enteric HAdVs differ notably in tissue tropism and pathogenicity from respiratory and ocular adenoviruses, but the structural basis for this divergence has been unknown. Here, we present the first structure of an enteric HAdV-HAdV-F41-determined by cryo-electron microscopy to a resolution of 3.8 angstrom. The structure reveals extensive alterations to the virion exterior as compared to nonenteric HAdVs, including a unique arrangement of capsid protein IX. The structure also provides new insights into conserved aspects of HAdV architecture such as a proposed location of core protein V, which links the viral DNA to the capsid, and assembly-induced conformational changes in the penton base protein. Our findings provide the structural basis for adaptation of enteric HAdVs to a fundamentally different tissue tropism.

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  • 14.
    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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  • 15.
    Rosendal, Ebba
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Mihai, Ionut Sebastian
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). National Clinical Research School in Chronic Inflammatory Diseases (NCRSCID), Karolinska Institutet, Solna, Sweden.
    Becker, Miriam
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between The Medical School Hannover, The Helmholtz Centre for Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Das, Debojyoti
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Persson, B. David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Swedish National Veterinary Institute (SVA), Uppsala, Sweden.
    Rankin, Gregory
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden.
    Gröning, Remigius
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Sartorius Corporate Research, Umeå, Sweden.
    Forsell, Mattias
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ankarklev, Johan
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Microbial Single Cell Genomics Facility, SciLifeLab, Biomedical Center (BMC) Uppsala University, Uppsala, Sweden.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Serine protease inhibitors restrict host susceptibility to SARS-CoV-2 infections2022In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 13, no 3, article id e00892-22Article in journal (Refereed)
    Abstract [en]

    The coronavirus disease 2019, COVID-19, is a complex disease with a wide range of symptoms from asymptomatic infections to severe acute respiratory syndrome with lethal outcome. Individual factors such as age, sex, and comorbidities increase the risk for severe infections, but other aspects, such as genetic variations, are also likely to affect the susceptibility to SARS-CoV-2 infection and disease severity. Here, we used a human 3D lung cell model based on primary cells derived from multiple donors to identity host factors that regulate SARS-CoV-2 infection. With a transcriptomics-based approach, we found that less susceptible donors show a higher expression level of serine protease inhibitors SERPINA1, SERPINE1, and SERPINE2, identifying variation in cellular serpin levels as restricting host factors for SARS-CoV-2 infection. We pinpoint their antiviral mechanism of action to inhibition of the cellular serine protease, TMPRSS2, thereby preventing cleavage of the viral spike protein and TMPRSS2-mediated entry into the target cells. By means of single-cell RNA sequencing, we further locate the expression of the individual serpins to basal, ciliated, club, and goblet cells. Our results add to the importance of genetic variations as determinants for SARS-CoV-2 susceptibility and suggest that genetic deficiencies of cellular serpins might represent risk factors for severe COVID-19. Our study further highlights TMPRSS2 as a promising target for antiviral intervention and opens the door for the usage of locally administered serpins as a treatment against COVID-19.

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  • 16. Welén, Karin
    et al.
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gisslén, Magnus
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Freyhult, Eva
    Fonseca Rodriguez, Osvaldo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bremell, Daniel
    Stranne, Johan
    Östholm Balkhed, Åse
    Niward, Katarina
    Repo, Johanna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Robinsson, David
    Henningsson, Anna J.
    Styrke, Johan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Angelin, Martin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindquist, Elisabeth
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Becker, Miriam
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Rudolfsson, Stina H.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Buckland, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Thellenberg Carlsson, Camilla
    Bjartell, Anders
    Nilsson, Anna C.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome: No Evidence of Benefit, Supported by Epidemiology and In Vitro Data2022In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 81, no 3, p. 285-293Article in journal (Refereed)
    Abstract [en]

    Background: Men are more severely affected by COVID-19. Testosterone may influence SARS-CoV-2 infection and the immune response.

    Objective: To clinically, epidemiologically, and experimentally evaluate the effect of antiandrogens on SARS-CoV-2 infection.

    Designs, settings, and participants: A randomized phase 2 clinical trial (COVIDENZA) enrolled 42 hospitalized COVID-19 patients before safety evaluation. We also conducted a population-based retrospective study of 7894 SARS-CoV-2–positive prostate cancer patients and an experimental study using an air-liquid interface three-dimensional culture model of primary lung cells.

    Intervention: In COVIDENZA, patients were randomized 2:1 to 5 d of enzalutamide or standard of care.

    Outcome measurements: The primary outcomes in COVIDENZA were the time to mechanical ventilation or discharge from hospital. The population-based study investigated risk of hospitalization, intensive care, and death from COVID-19 after androgen inhibition.

    Results and limitations: Enzalutamide-treated patients required longer hospitalization (hazard ratio [HR] for discharge from hospital 0.43, 95% confidence interval [CI] 0.20–0.93) and the trial was terminated early. In the epidemiological study, no preventive effects were observed. The frail population of patients treated with androgen deprivation therapy (ADT) in combination with abiraterone acetate or enzalutamide had a higher risk of dying from COVID-19 (HR 2.51, 95% CI 1.52–4.16). In vitro data showed no effect of enzalutamide on virus replication. The epidemiological study has limitations that include residual confounders.

    Conclusions: The results do not support a therapeutic effect of enzalutamide or preventive effects of bicalutamide or ADT in COVID-19. Thus, these antiandrogens should not be used for hospitalized COVID-19 patients or as prevention for COVID-19. Further research on these therapeutics in this setting are not warranted.

    Patient summary: We studied whether inhibition of testosterone could diminish COVID-19 symptoms. We found no evidence of an effect in a clinical study or in epidemiological or experimental investigations. We conclude that androgen inhibition should not be used for prevention or treatment of COVID-19.

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  • 17.
    Zapatero-Belinchón, Francisco J.
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Moeller, Rebecca
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Lasswitz, Lisa
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    van Ham, Marco
    Cellular Proteome Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Becker, Miriam
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Brogden, Graham
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. The Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå, Sweden.
    Bi, Wenjie
    Cellular Proteome Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Carriquí-Madroñal, Belén
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Islam, Md. Koushikul
    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.
    Lenman, Annasara
    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.
    Gunesch, Antonia P.
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Centre for Infection Research (DZIF), Partner site Hannover-Braunschweig, Hannover, Germany.
    Kirui, Jared
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Pietschmann, Thomas
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; German Centre for Infection Research (DZIF), Partner site Hannover-Braunschweig, Hannover, Germany.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Jänsch, Lothar
    Cellular Proteome Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Fluvastatin mitigates SARS-CoV-2 infection in human lung cells2021In: iScience, E-ISSN 2589-0042, Vol. 24, no 12, article id 103469Article in journal (Refereed)
    Abstract [en]

    Clinical data of patients suffering from COVID-19 indicates that statin therapy, used to treat hypercholesterolemia, is associated with a better disease outcome. Whether statins directly affect virus replication or influence the clinical outcome through modulation of immune responses is unknown. We therefore investigated the effect of statins on SARS-CoV-2 infection in human lung cells and found that only fluvastatin inhibited low and high pathogenic coronaviruses in vitro and ex vivo in a dose-dependent manner. Quantitative proteomics revealed that fluvastatin and other tested statins modulated the cholesterol synthesis pathway without altering innate antiviral immune responses in infected lung epithelial cells. However, fluvastatin treatment specifically downregulated proteins that modulate protein translation and viral replication. Collectively, these results support the notion that statin therapy poses no additional risk to individuals exposed to SARS-CoV-2 and that fluvastatin has a moderate beneficial effect on SARS-CoV-2 infection of human lung cells.

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