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  • 1. Asghar, Naveed
    et al.
    Lee, Yi-Ping
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Nilsson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Lindqvist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Melik, Wessam
    Kröger, Andrea
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Johansson, Magnus
    The role of the poly(A) tract in the replication and virulence of tick-borne encephalitis virus2016Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 6, artikkel-id 39265Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The tick-borne encephalitis virus (TBEV) is a flavivirus transmitted to humans, usually via tick bites. The virus causes tick-borne encephalitis (TBE) in humans, and symptoms range from mild flu-like symptoms to severe and long-lasting sequelae, including permanent brain damage. It has been suggested that within the population of viruses transmitted to the mammalian host, quasispecies with neurotropic properties might become dominant in the host resulting in neurological symptoms. We previously demonstrated the existence of TBEV variants with variable poly(A) tracts within a single blood-fed tick. To characterize the role of the poly(A) tract in TBEV replication and virulence, we generated infectious clones of Toro-2003 with the wild-type (A)(3)C(A)(6) sequence (Toro-6A) or with a modified (A)(3)C(A)(38) sequence (Toro-38A). Toro-38A replicated poorly compared to Toro-6A in cell culture, but Toro-38A was more virulent than Toro-6A in a mouse model of TBE. Next-generation sequencing of TBEV genomes after passaging in cell culture and/or mouse brain revealed mutations in specific genomic regions and the presence of quasispecies that might contribute to the observed differences in virulence. These data suggest a role for quasispecies development within the poly(A) tract as a virulence determinant for TBEV in mice.

    Fulltekst (pdf)
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  • 2. Asghar, Naveed
    et al.
    Lindblom, Pontus
    Melik, Wessam
    Lindqvist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Haglund, Mats
    Forsberg, Pia
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Andreassen, Åshild
    Lindgren, Per-Eric
    Johansson, Magnus
    Tick-borne encephalitis virus sequenced directly from questing and blood-feeding ticks reveals quasispecies variance2014Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 9, nr 7, s. e103264-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The increased distribution of the tick-borne encephalitis virus (TBEV) in Scandinavia highlights the importance of characterizing novel sequences within the natural foci. In this study, two TBEV strains: the Norwegian Mandal 2009 (questing nymphs pool) and the Swedish Saringe 2009 (blood-fed nymph) were sequenced and phylogenetically characterized. Interestingly, the sequence of Mandal 2009 revealed the shorter form of the TBEV genome, similar to the highly virulent Hypr strain, within the 3' non-coding region (3'NCR). A different genomic structure was found in the 3'NCR of Saringe 2009, as in-depth analysis demonstrated TBEV variants with different lengths within the poly(A) tract. This shows that TBEV quasispecies exists in nature and indicates a putative shift in the quasispecies pool when the virus switches between invertebrate and vertebrate environments. This prompted us to further sequence and analyze the 3'NCRs of additional Scandinavian TBEV strains and control strains, Hypr and Neudoerfl. Toro 2003 and Habo 2011 contained mainly a short (A) 3C(A)6 poly(A) tract. A similar pattern was observed for the human TBEV isolates 1993/783 and 1991/4944; however, one clone of 1991/4944 contained an (A) 3C(A)11 poly(A) sequence, demonstrating that quasispecies with longer poly(A) could be present in human isolates. Neudoerfl has previously been reported to contain a poly(A) region, but to our surprise the resequenced genome contained two major quasispecies variants, both lacking the poly(A) tract. We speculate that the observed differences are important factors for the understanding of virulence, spread, and control of the TBEV.

    Fulltekst (pdf)
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  • 3.
    Chotiwan, Nunya
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand.
    Rosendal, Ebba
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Willekens, Stefanie M. A.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Schexnaydre, Erin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Nilsson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Lindquist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Hahn, Max
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Mihai, Ionut Sebastian
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Morini, Federico
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Zhang, Jianguo
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Ebel, Gregory D.
    Department of Microbiology, Immunology and Pathology, Colorado State University, CO, Fort Collins, United States.
    Carlson, Lars-Anders
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Henriksson, Johan
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Type I interferon shapes brain distribution and tropism of tick-borne flavivirus2023Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikkel-id 2007Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Viral tropism within the brain and the role(s) of vertebrate immune response to neurotropic flaviviruses infection is largely understudied. We combine multimodal imaging (cm-nm scale) with single nuclei RNA-sequencing to study Langat virus in wildtype and interferon alpha/beta receptor knockout (Ifnar-/-) mice to visualize viral pathogenesis and define molecular mechanisms. Whole brain viral infection is imaged by Optical Projection Tomography coregistered to ex vivo MRI. Infection is limited to grey matter of sensory systems in wildtype mice, but extends into white matter, meninges and choroid plexus in Ifnar-/- mice. Cells in wildtype display strong type I and II IFN responses, likely due to Ifnb expressing astrocytes, infiltration of macrophages and Ifng-expressing CD8+ NK cells, whereas in Ifnar-/-, the absence of this response contributes to a shift in cellular tropism towards non-activated resident microglia. Multimodal imaging-transcriptomics exemplifies a powerful way to characterize mechanisms of viral pathogenesis and tropism.

    Fulltekst (pdf)
    fulltext
  • 4. Dobler, G.
    et al.
    Bestehorn, M.
    Antwerpen, M.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Complete Genome Sequence of a Low-Virulence Tick-Borne Encephalitis Virus Strain2016Inngår i: Microbiology Resource Announcements, E-ISSN 2576-098X, Vol. 4, nr 5, artikkel-id e01145-16Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We report here the complete genome sequence (GenBank accession no. KX268728) of tick-borne encephalitis strain HB171/11, isolated from an Ixodes ricinus tick from a natural focus where human neurological disease is rare. The strain shows unique characteristics in neuroinvasiveness and neurovirulence.

    Fulltekst (pdf)
    fulltext
  • 5. Flick, Kirsten
    et al.
    Katz, Anna
    Överby, Anna
    Ludwig Institute for Cancer Research, Stockholm Branch, Karolinska Institute, Stockholm, Sweden.
    Feldmann, Heinz
    Pettersson, Ralf F
    Flick, Ramon
    Functional analysis of the noncoding regions of the Uukuniemi virus (Bunyaviridae) RNA segments2004Inngår i: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 78, nr 21, s. 11726-11738Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The role of the variable portion of the noncoding regions (NCRs) of the three Bunyaviridae RNA segments (L, M, S) in transcription, replication, and packaging was studied using the recently developed plasmid-driven RNA polymerase I minigenome system for Uukuniemi (UUK) virus, genus Phlebovirus (11), as a model. Comparison of the different segments showed that all NCRs were sufficient to mediate transcription/replication of a minigenome but demonstrated decreased promoter strength in the order M > L > S. Chimeric minigenomes with flanking NCRs from different genome segments revealed that the number of total base pairs within the inverted, partially complementary ends was important for transcription and replication. Point mutations increasing the base-pairing potential produced increased reporter expression, indicating that complementarity between the 5' and 3' ends is crucial for promoter activity. The role of the intergenic region (IGR) located between the two open reading frames of the ambisense UUK virus S segment was analyzed by inserting this sequence element downstream of the reporter genes. The presence of the IGR was found to enhance reporter expression, demonstrating that efficient transcription termination, regulated by the IGR, is important for optimal minigenome mRNA translation. Finally, genome packaging efficacy varied for different NCRs and was strongest for L followed by M and S. Strong reporter gene activity was still observed after seven consecutive cell culture passages, indicating a selective rather than random genome-packaging mechanism. In summary, our results demonstrate that the NCRs from all three segments contain the necessary signals to initiate transcription and replication as well as packaging. Based on promoter strength, M-segment NCRs may be the preferred choice for the development of reverse genetics and minigenome rescue systems for bunyaviruses.

  • 6.
    Garvanska, Dimitriya H.
    et al.
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Alvarado, R. Elias
    Department of Microbiology and Immunology, University of Texas Medical Branch, TX, Galveston, United States; Institute for Translational Sciences, University of Texas Medical Branch, TX, Galveston, United States.
    Mundt, Filip Oskar
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Lindquist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Duel, Josephine Kerzel
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Coscia, Fabian
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Nilsson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Lokugamage, Kumari
    Department of Microbiology and Immunology, University of Texas Medical Branch, TX, Galveston, United States.
    Johnson, Bryan A.
    Department of Microbiology and Immunology, University of Texas Medical Branch, TX, Galveston, United States.
    Plante, Jessica A.
    Department of Microbiology and Immunology, University of Texas Medical Branch, TX, Galveston, United States; World Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, TX, Galveston, United States.
    Morris, Dorothea R.
    Department of Microbiology and Immunology, University of Texas Medical Branch, TX, Galveston, United States; Institute for Translational Sciences, University of Texas Medical Branch, TX, Galveston, United States.
    Vu, Michelle N.
    Department of Microbiology and Immunology, University of Texas Medical Branch, TX, Galveston, United States.
    Estes, Leah K.
    Department of Microbiology and Immunology, University of Texas Medical Branch, TX, Galveston, United States.
    McLeland, Alyssa M.
    Department of Microbiology and Immunology, University of Texas Medical Branch, TX, Galveston, United States.
    Walker, Jordyn
    Department of Microbiology and Immunology, University of Texas Medical Branch, TX, Galveston, United States; World Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, TX, Galveston, United States.
    Crocquet-Valdes, Patricia A.
    Department of Pathology, University of Texas Medical Branch, TX, Galveston, United States.
    Mendez, Blanca Lopez
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Plante, Kenneth S.
    Department of Microbiology and Immunology, University of Texas Medical Branch, TX, Galveston, United States; World Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, TX, Galveston, United States.
    Walker, David H.
    Department of Pathology, University of Texas Medical Branch, TX, Galveston, United States.
    Weisser, Melanie Bianca
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Mann, Matthias
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Menachery, Vineet D.
    Department of Microbiology and Immunology, University of Texas Medical Branch, TX, Galveston, United States; World Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, TX, Galveston, United States.
    Nilsson, Jakob
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions2024Inngår i: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 25, nr 2, s. 902-926Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1, FXR1-2). SARS-CoV-2 NSP3 mutant viruses preventing FMRP binding have attenuated replication in vitro and reduced levels of viral antigen in lungs during the early stages of infection. We show that a unique peptide motif in NSP3 binds directly to the two central KH domains of FMRPs and that this interaction is disrupted by the I304N mutation found in a patient with fragile X syndrome. NSP3 binding to FMRPs disrupts their interaction with the stress granule component UBAP2L through direct competition with a peptide motif in UBAP2L to prevent FMRP incorporation into stress granules. Collectively, our results provide novel insight into how SARS-CoV-2 hijacks host cell proteins and provides molecular insight into the possible underlying molecular defects in fragile X syndrome.

    Fulltekst (pdf)
    fulltext
  • 7.
    Gwon, Yong-Dae
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Strand, Mårten
    Lindquist, Richard
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi.
    Nilsson, Emma
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi.
    Saleeb, Michael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Evander, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Antiviral Activity of Benzavir-2 against Emerging Flaviviruses2020Inngår i: Viruses, E-ISSN 1999-4915, Vol. 12, nr 3, artikkel-id 351Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

    Fulltekst (pdf)
    fulltext
  • 8. Habjan, Matthias
    et al.
    Penski, Nicola
    Wagner, Valentina
    Spiegel, Martin
    Överby, Anna K
    Department of Virology, University of Freiburg, D-79008 Freiburg, Germany.
    Kochs, Georg
    Huiskonen, Juha T
    Weber, Friedemann
    Efficient production of Rift Valley fever virus-like particles: the antiviral protein MxA can inhibit primary transcription of bunyaviruses2009Inngår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 385, nr 2, s. 400-408Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rift Valley fever virus (RVFV) is a highly pathogenic member of the family Bunyaviridae that needs to be handled under biosafety level (BSL) 3 conditions. Here, we describe reverse genetics systems to measure RVFV polymerase activity in mammalian cells and to generate virus-like particles (VLPs). Recombinant polymerase (L) and nucleocapsid protein (N), expressed together with a minireplicon RNA, formed transcriptionally active nucleocapsids. These could be packaged into VLPs by additional expression of viral glycoproteins. The VLPs resembled authentic virus particles and were able to infect new cells. After infection, VLP-associated nucleocapsids autonomously performed primary transcription, and co-expression of L and N in VLP-infected cells allowed subsequent replication and secondary transcription. Bunyaviruses are potently inhibited by a human interferon-induced protein, MxA. However, the affected step in the infection cycle is not entirely characterized. Using the VLP system, we demonstrate that MxA inhibits both primary and secondary transcriptions of RVFV. A set of infection assays distinguishing between virus attachment, entry, and subsequent RNA synthesis confirmed that MxA is able to target immediate early RNA synthesis of incoming RVFV particles. Thus, our reverse genetics systems are useful for dissecting individual steps of RVFV infection under non-BSL3 conditions.

  • 9. Habjan, Matthias
    et al.
    Pichlmair, Andreas
    Elliott, Richard M
    Överby, Anna K
    Department of Virology, University of Freiburg, Freiburg, Germany.
    Glatter, Timo
    Gstaiger, Matthias
    Superti-Furga, Giulio
    Unger, Hermann
    Weber, Friedemann
    NSs protein of rift valley fever virus induces the specific degradation of the double-stranded RNA-dependent protein kinase2009Inngår i: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 83, nr 9, s. 4365-4375Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rift Valley fever virus (RVFV) continues to cause large outbreaks of acute febrile and often fatal illness among humans and domesticated animals in Africa, Saudi Arabia, and Yemen. The high pathogenicity of this bunyavirus is mainly due to the viral protein NSs, which was shown to prevent transcriptional induction of the antivirally active type I interferons (alpha/beta interferon [IFN-alpha/beta]). Viruses lacking the NSs gene induce synthesis of IFNs and are therefore attenuated, whereas the noninducing wild-type RVFV strains can only be inhibited by pretreatment with IFN. We demonstrate here in vitro and in vivo that a substantial part of the antiviral activity of IFN against RVFV is due to a double-stranded RNA-dependent protein kinase (PKR). PKR-mediated virus inhibition, however, was much more pronounced for the strain Clone 13 with NSs deleted than for the NSs-expressing strain ZH548. In vivo, Clone 13 was nonpathogenic for wild-type (wt) mice but could regain pathogenicity if mice lacked the PKR gene. ZH548, in contrast, killed both wt and PKR knockout mice indiscriminately. ZH548 was largely resistant to the antiviral properties of PKR because RVFV NSs triggered the specific degradation of PKR via the proteasome. The NSs proteins of the related but less virulent sandfly fever Sicilian virus and La Crosse virus, in contrast, had no such anti-PKR activity despite being efficient suppressors of IFN induction. Our data suggest that RVFV NSs has gained an additional anti-IFN function that may explain the extraordinary pathogenicity of this virus.

  • 10. Henningsson, Anna J.
    et al.
    Lindqvist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Norberg, Peter
    Lindblom, Pontus
    Roth, Anette
    Forsberg, Pia
    Bergström, Tomas
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Lindgren, Per-Eric
    Human Tick-Borne Encephalitis and Characterization of Virus from Biting Tick2016Inngår i: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 22, nr 8, s. 1485-1487Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We report a case of human tick-borne encephalitis (TBE) in which the TBE virus was isolated from the biting tick. Viral growth and sequence were characterized and compared with those of a reference strain. Virus isolation from ticks from patients with TBE may offer a new approach for studies of epidemiology and pathogenicity.

  • 11.
    Holm, Karin
    et al.
    Department of Infectious diseases, Skåne University Hospital, Lund, Sweden.
    Lundgren, Maria N.
    Department of Clinical Immunology and Transfusion Medicine, University and Regional Laboratories, Region Skåne, Sweden.
    Kjeldsen-Kragh, Jens
    Department of Clinical Immunology and Transfusion Medicine, University and Regional Laboratories, Region Skåne, Sweden.
    Ljungquist, Oskar
    Clinical Infection Medicine, Department of Translational Medicine, Lund University, Malmö, Sweden.
    Böttiger, Blenda
    Department of Clinical Microbiology, University and Regional Laboratories, Region Skåne, Sweden.
    Wikén, Christian
    Department of Infectious diseases, Skåne University Hospital, Lund, Sweden.
    Öberg, Jonas
    Department of Infectious diseases, Skåne University Hospital, Lund, Sweden.
    Fernström, Nils
    Department of Infectious diseases, Skåne University Hospital, Lund, Sweden.
    Rosendal, Ebba
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Wigren, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Landin-Olsson, Mona
    Department of Endocrinology, Skåne University Hospital, Lund, Sweden.
    Rasmussen, Magnus
    Department of Infectious diseases, Skåne University Hospital, Lund, Sweden.
    Convalescence plasma treatment of COVID-19: results from a prematurely terminated randomized controlled open-label study in Southern Sweden2021Inngår i: BMC Research Notes, E-ISSN 1756-0500, Vol. 14, nr 1, artikkel-id 440Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Convalescent plasma has been tried as therapy for various viral infections. Early observational studies of convalescent plasma treatment for hospitalized COVID-19 patients were promising, but randomized controlled studies were lacking at the time. The objective of this study was to investigate if convalescent plasma is beneficial to hospitalized patients with COVID-19.

    Results: Hospitalized patients with confirmed COVID-19 and an oxygen saturation below 94% were randomized 1:1 to receive convalescent plasma in addition to standard of care or standard of care only. The primary outcome was number of days of oxygen treatment to keep saturation above 93% within 28 days from inclusion. The study was prematurely terminated when thirty-one of 100 intended patients had been included. The median time of oxygen treatment among survivors was 11 days (IQR 6–15) for the convalescent plasma group and 7 days (IQR 5–9) for the standard of care group (p = 0.4, median difference -4). Two patients in the convalescent plasma group and three patients in the standard of care group died (p = 0.64, OR 0.49, 95% CI 0.08–2.79). Thus no significant differences were observed between the groups.

    Fulltekst (pdf)
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  • 12. Huiskonen, Juha T
    et al.
    Överby, Anna K
    Department of Virology, University of Freiburg, Hermann-Herder-Strasse 11, D-79008 Freiburg, Germany.
    Weber, Friedemann
    Grünewald, Kay
    Electron cryo-microscopy and single-particle averaging of Rift Valley fever virus: evidence for GN-GC glycoprotein heterodimers2009Inngår i: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 83, nr 8, s. 3762-3769Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rift Valley fever virus (RVFV) is a member of the genus Phlebovirus within the family Bunyaviridae. It is a mosquito-borne zoonotic agent that can cause hemorrhagic fever in humans. The enveloped RVFV virions are known to be covered by capsomers of the glycoproteins G(N) and G(C), organized on a T=12 icosahedral lattice. However, the structural units forming the RVFV capsomers have not been determined. Conflicting biochemical results for another phlebovirus (Uukuniemi virus) have indicated the existence of either G(N) and G(C) homodimers or G(N)-G(C) heterodimers in virions. Here, we have studied the structure of RVFV using electron cryo-microscopy combined with three-dimensional reconstruction and single-particle averaging. The reconstruction at 2.2-nm resolution revealed the organization of the glycoprotein shell, the lipid bilayer, and a layer of ribonucleoprotein (RNP). Five- and six-coordinated capsomers are formed by the same basic structural unit. Molecular-mass measurements suggest a G(N)-G(C) heterodimer as the most likely candidate for this structural unit. Both leaflets of the lipid bilayer were discernible, and the glycoprotein transmembrane densities were seen to modulate the curvature of the lipid bilayer. RNP densities were situated directly underneath the transmembrane densities, suggesting an interaction between the glycoprotein cytoplasmic tails and the RNPs. The success of the single-particle averaging approach taken in this study suggests that it is applicable in the study of other phleboviruses, as well, enabling higher-resolution description of these medically important pathogens.

  • 13.
    Islam, Md. Koushikul
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Baudin, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Eriksson, Jonas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Öberg, Christopher
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Habjan, Matthias
    Weber, Friedemann
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Evander, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection2016Inngår i: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 21, nr 4, s. 354-362Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rift Valley fever virus (RVFV) is an emerging virus that causes serious illness in humans and livestock. There are no approved vaccines or treatments for humans. The purpose of the study was to identify inhibitory compounds of RVFV infection without any preconceived idea of the mechanism of action. A whole-cell-based high-throughput drug screening assay was developed to screen 28,437 small chemical compounds targeting RVFV infection. To accomplish both speed and robustness, a replication-competent NSs-deleted RVFV expressing a fluorescent reporter gene was developed. Inhibition of fluorescence intensity was quantified by spectrophotometry and related to virus infection in human lung epithelial cells (A549). Cell toxicity was assessed by the Resazurin cell viability assay. After primary screening, 641 compounds were identified that inhibited RVFV infection by 80%, with 50% cell viability at 50 mu M concentration. These compounds were subjected to a second screening regarding dose-response profiles, and 63 compounds with 60% inhibition of RVFV infection at 3.12 mu M compound concentration and 50% cell viability at 25 mu M were considered hits. Of these, six compounds with high inhibitory activity were identified. In conclusion, the high-throughput assay could efficiently and safely identify several promising compounds that inhibited RVFV infection.

  • 14.
    Kruse, Thomas
    et al.
    The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health and Medical Sciences, Blegdamsvej 3B, Copenhagen, Denmark.
    Benz, Caroline
    Department of Chemistry - BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Garvanska, Dimitriya H.
    The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health and Medical Sciences, Blegdamsvej 3B, Copenhagen, Denmark.
    Lindquist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Mihalic, Filip
    Department of Medical Biochemistry and Microbiology, Uppsala University, BMC, Box 582, Husargatan 3, Uppsala, Sweden.
    Coscia, Fabian
    The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health and Medical Sciences, Blegdamsvej 3B, Copenhagen, Denmark; Spatial Proteomics Group, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
    Inturi, Raviteja
    Department of Medical Biochemistry and Microbiology, Uppsala University, BMC, Box 582, Husargatan 3, Uppsala, Sweden.
    Sayadi, Ahmed
    Department of Chemistry - BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Simonetti, Leandro
    Department of Chemistry - BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Nilsson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Ali, Muhammad
    Department of Chemistry - BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Kliche, Johanna
    Department of Chemistry - BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Moliner Morro, Ainhoa
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Mund, Andreas
    The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health and Medical Sciences, Blegdamsvej 3B, Copenhagen, Denmark.
    Andersson, Eva
    Department of Medical Biochemistry and Microbiology, Uppsala University, BMC, Box 582, Husargatan 3, Uppsala, Sweden.
    McInerney, Gerald
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Mann, Matthias
    The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health and Medical Sciences, Blegdamsvej 3B, Copenhagen, Denmark.
    Jemth, Per
    Department of Medical Biochemistry and Microbiology, Uppsala University, BMC, Box 582, Husargatan 3, Uppsala, Sweden.
    Davey, Norman E.
    Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, United Kingdom.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Nilsson, Jakob
    The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health and Medical Sciences, Blegdamsvej 3B, Copenhagen, Denmark.
    Ivarsson, Ylva
    Department of Chemistry - BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities2021Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 12, nr 1, artikkel-id 6761Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Viral proteins make extensive use of short peptide interaction motifs to hijack cellular host factors. However, most current large-scale methods do not identify this important class of protein-protein interactions. Uncovering peptide mediated interactions provides both a molecular understanding of viral interactions with their host and the foundation for developing novel antiviral reagents. Here we describe a viral peptide discovery approach covering 23 coronavirus strains that provides high resolution information on direct virus-host interactions. We identify 269 peptide-based interactions for 18 coronaviruses including a specific interaction between the human G3BP1/2 proteins and an ΦxFG peptide motif in the SARS-CoV-2 nucleocapsid (N) protein. This interaction supports viral replication and through its ΦxFG motif N rewires the G3BP1/2 interactome to disrupt stress granules. A peptide-based inhibitor disrupting the G3BP1/2-N interaction dampened SARS-CoV-2 infection showing that our results can be directly translated into novel specific antiviral reagents.

    Fulltekst (pdf)
    fulltext
  • 15.
    Kurhade, Chaitanya
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Lee, Yi-Ping
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Schreier, Sarah
    Zegenhagen, Loreen
    Kröger, Andrea
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Correlation of disease severity in human tick-borne encephalitis and pathogenicity in miceManuskript (preprint) (Annet vitenskapelig)
  • 16.
    Kurhade, Chaitanya
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Schreier, Sarah
    Lee, Yi-Ping
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. National Cheng Kung University, Tainan, Taiwan..
    Zegenhagen, Loreen
    Hjertqvist, Marika
    Dobler, Gerhard
    Kroeger, Andrea
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Correlation of Severity of Human Tick-Borne Encephalitis Virus Disease and Pathogenicity in Mice2018Inngår i: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 24, nr 9, s. 1709-1712Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We compared 2 tick-borne encephalitis virus strains isolated from 2 different foci that cause different symptoms in tick-borne encephalitis patients, from neurologic to mild gastrointestinal symptoms. We compared neuroinvasiveness, neurovirulence, and proinflammatory cytokine response in mice and found unique differences that contribute to our understanding of pathogenesis.

    Fulltekst (pdf)
    fulltext
  • 17.
    Kurhade, Chaitanya
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Zegenhagen, Loreen
    Weber, Elvira
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Nair, Sharmila
    Michaelsen-Preusse, Kristin
    Spanier, Julia
    Gekara, Nelson O.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Kroeger, Andrea
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Type I Interferon response in olfactory bulb, the site of tick-borne flavivirus accumulation, is primarily regulated by IPS-12016Inngår i: Journal of Neuroinflammation, E-ISSN 1742-2094, Vol. 13, artikkel-id 22Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Although type I interferons (IFNs)—key effectors of antiviral innate immunity are known to be induced via different pattern recognition receptors (PRRs), the cellular source and the relative contribution of different PRRs in host protection against viral infection is often unclear. IPS-1 is a downstream adaptor for retinoid-inducible gene I (RIG-I)-like receptor signaling. In this study, we investigate the relative contribution of IPS-1 in the innate immune response in the different brain regions during infection with tick-borne encephalitis virus (TBEV), a flavivirus that causes a variety of severe symptoms like hemorrhagic fevers, encephalitis, and meningitis in the human host.

    Methods: IPS-1 knockout mice were infected with TBEV/Langat virus (LGTV), and viral burden in the peripheral and the central nervous systems, type I IFN induction, brain infiltrating cells, and inflammatory response was analyzed.

    Results: We show that IPS-1 is indispensable for controlling TBEV and LGTV infections in the peripheral and central nervous system. Our data indicate that IPS-1 regulates neuropathogenicity in mice. IFN response is differentially regulated in distinct regions of the central nervous system (CNS) influencing viral tropism, as LGTV replication was mainly restricted to olfactory bulb in wild-type (WT) mice. In contrast to the other brain regions, IFN upregulation in the olfactory bulb was dependent on IPS-1 signaling. IPS-1 regulates basal levels of antiviral interferon-stimulated genes (ISGs) like viperin and IRF-1 which contributes to the establishment of early viral replication which inhibits STAT1 activation. This diminishes the antiviral response even in the presence of high IFN-β levels. Consequently, the absence of IPS-1 causes uncontrolled virus replication, in turn resulting in apoptosis, activation of microglia and astrocytes, elevated proinflammatory response, and recruitment of inflammatory cells into the CNS.

    Conclusions: We show that LGTV replication is restricted to the olfactory bulb and that IPS-1 is a very important player in the olfactory bulb in shaping the innate immune response by inhibiting early viral replication and viral spread throughout the central nervous system. In the absence of IPS-1, higher viral replication leads to the evasion of antiviral response by inhibiting interferon signaling. Our data suggest that the local microenvironment of distinct brain regions is critical to determine virus permissiveness.

    Fulltekst (pdf)
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  • 18. Lindgren, Lena
    et al.
    Lindkvist, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Överby, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Bucht, Göran
    Holmström, Anna
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Regions of importance for interaction of puumala virus nucleocapsid subunits2006Inngår i: Virus genes, ISSN 0920-8569, E-ISSN 1572-994X, Vol. 33, nr 2, s. 169-174Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Puumala virus (PUUV) is a hantavirus that causes a mild form of hemorrhagic fever with renal syndrome in northern and central Europe, and in large parts of Russia. The nucleocapsid (N) protein encoded by hantaviruses plays an important role in the life-cycle of these viruses, and one important function for the N-protein is to oligomerize, surround and protect the viral RNAs. We have identified amino- and carboxy-terminal regions involved in PUUV N-N interactions, which comprise amino acids 100-120 and 330-405. Our findings strengthen the hypothesis that the amino-terminus of the N-protein of hantaviruses holds a more regulatory function regarding N-N interactions, while conserved residues in the carboxy-terminal region, F335 together with F336 and W392, in concert with Y388 and/or F400 seems to play a more critical role in the PUUV N-N formation. This study provides evidence that the amino-terminal regions involved in the N-N interaction of Puumala virus are similar to those reported for Seoul virus (SEOV) and to some extent Hantaan virus (HTNV), even though the identity between PUUV N and SEOV/HTNV N is markedly lower than between PUUV N and Tula virus (TULV) N or Sin Nombre virus (SNV) N.

  • 19.
    Lindquist, Richard
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Benz, Caroline
    Department of Chemistry—BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Sereikaite, Vita
    Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark.
    Maassen, Lars
    Department of Chemistry—BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Laursen, Louise
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, Uppsala, Sweden.
    Jemth, Per
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, Uppsala, Sweden.
    Strømgaard, Kristian
    Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark.
    Ivarsson, Ylva
    Department of Chemistry—BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    A syntenin inhibitor blocks endosomal entry of SARS-CoV-2 and a panel of RNA viruses2022Inngår i: Viruses, E-ISSN 1999-4915, Vol. 14, nr 10, artikkel-id 2202Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

    Fulltekst (pdf)
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  • 20.
    Lindquist, Richard
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Rosendal, Ebba
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi.
    Weber, Elvira
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (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 universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi. 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 universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi.
    The envelope protein of tick-borne encephalitis virus influences neuron entry, pathogenicity, and vaccine protection2020Inngår i: Journal of Neuroinflammation, E-ISSN 1742-2094, Vol. 17, nr 1, artikkel-id 284Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
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  • 21.
    Lindquist, Richard
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    The Role of Viperin in Antiflavivirus Responses2018Inngår i: DNA and Cell Biology, ISSN 1044-5498, E-ISSN 1557-7430, Vol. 37, nr 9, s. 725-730Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Viperin is an interferon (IFN)-stimulated gene product, which is part of the first line of the intracellular response against viral infection. It is a potent antiviral protein, strongly upregulated after IFN-stimulation and virus infection. Viperin is antivirally active against many different viruses from different families and has been shown to inhibit several flaviviruses. Flaviviruses are an important group of arthropod-borne viruses that cause millions of infections annually. In this review, we focus on the recent advances of the antiviral mechanisms of viperin against these flaviviruses, both pointing to similarities and differences between viruses within the same genera.

  • 22.
    Lindqvist, Richard
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Kurhade, Chaitanya
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Gilthorpe, Jonathan D.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Cell-type- and region-specific restriction of neurotropic flavivirus infection by viperin2018Inngår i: Journal of Neuroinflammation, E-ISSN 1742-2094, Vol. 15, artikkel-id 80Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Flaviviruses are a group of diverse and emerging arboviruses and an immense global health problem. A number of flaviviruses are neurotropic, causing severe encephalitis and even death. Type I interferons (IFNs) are the first line of defense of the innate immune system against flavivirus infection. IFNs elicit the concerted action of numerous interferon-stimulated genes (ISGs) to restrict both virus infection and replication. Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, IFN-inducible) is an ISG with broad-spectrum antiviral activity against multiple flaviviruses in vitro. Its activity in vivo restricts neurotropic infections to specific regions of the central nervous system (CNS). However, the cell types in which viperin activity is required are unknown. Here we have examined both the regional and cell-type specificity of viperin in the defense against infection by several model neurotropic flaviviruses.

    Methods: Viral burden and IFN induction were analyzed in vivo in wild-type and viperin(-/-) mice infected with Langat virus (LGTV). The effects of IFN pretreatment were tested in vitro in primary neural cultures from different brain regions in response to infection with tick-borne encephalitis virus (TBEV), West Nile virus (WNV), and Zika virus (ZIKV).

    Results: Viperin activity restricted nonlethal LGTV infection in the spleen and the olfactory bulb following infection via a peripheral route. Viperin activity was also necessary to restrict LGTV replication in the olfactory bulb and the cerebrum following CNS infection, but not in the cerebellum. In vitro, viperin could restrict TBEV replication in primary cortical neurons, but not in the cerebellar granule cell neurons. Interferon-induced viperin was also very important in primary cortical neurons to control TBEV, WNV, and ZIKV.

    Conclusions: Our findings show that viperin restricts replication of neurotropic flaviviruses in the CNS in a region- and cell-type-specific manner. The most important sites of activity are the olfactory bulb and cerebrum. Activity within the cerebrum is required in the cortical neurons in order to restrict spread. This study exemplifies cell type and regional diversity of the IFN response within the CNS and shows the importance of a potent broad-spectrum antiviral ISG.

    Fulltekst (pdf)
    fulltext
  • 23.
    Lindqvist, Richard
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Kurhade, Chaitanya
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Gilthorpe, Jonathan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Viperin restrict neurotropic flavivirus infection in cell type and region-specific mannerManuskript (preprint) (Annet vitenskapelig)
  • 24.
    Lindqvist, Richard
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Mundt, Filip
    Gilthorpe, Jonathan D.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Woelfel, Silke
    Gekara, Nelson O.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Kroeger, Andrea
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects2016Inngår i: Journal of Neuroinflammation, E-ISSN 1742-2094, Vol. 13, artikkel-id 277Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Neurotropic flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne flavivirus infection. However, the cells responsible for mounting this protective response are not defined. Methods: Primary astrocytes were isolated from wild-type (WT) and interferon alpha receptor knock out (IFNAR(-/-)) mice and infected with neurotropic flaviviruses. Viral replication and spread, IFN induction and response, and cellular viability were analyzed. Transcriptional levels in primary astrocytes treated with interferon or supernatant from virus-infected cells were analyzed by RNA sequencing and evaluated by different bioinformatics tools. Results: Here, we show that astrocytes control viral replication of different TBEV strains, JEV, WNV, and ZIKV. In contrast to fibroblast, astrocytes mount a rapid interferon response and restrict viral spread. Furthermore, basal expression levels of key interferon-stimulated genes are high in astrocytes compared to mouse embryonic fibroblasts. Bioinformatic analysis of RNA-sequencing data reveals that astrocytes have established a basal antiviral state which contributes to the rapid viral recognition and upregulation of interferons. The most highly upregulated pathways in neighboring cells were linked to type I interferon response and innate immunity. The restriction in viral growth was dependent on interferon signaling, since loss of the interferon receptor, or its blockade in wild-type cells, resulted in high viral replication and virus-induced cytopathic effects. Astrocyte supernatant from TBEV-infected cells can restrict TBEV growth in astrocytes already 6 h post infection, the effect on neurons is highly reinforced, and astrocyte supernatant from 3 h post infection is already protective. Conclusions: These findings suggest that the combination of an intrinsic constitutive antiviral response and the fast induction of type I IFN production by astrocytes play an important role in self-protection of astrocytes and suppression of flavivirus replication in the CNS.

    Fulltekst (pdf)
    fulltext
  • 25.
    Lindqvist, Richard
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Upadhyay, Arunkumar S.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Tick-Borne Flaviviruses and the Type I Interferon Response2018Inngår i: Viruses, E-ISSN 1999-4915, Vol. 10, nr 7, artikkel-id 340Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

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

    Fulltekst (pdf)
    fulltext
  • 26.
    Ljungquist, Oskar
    et al.
    Department of Translational Medicine, Clinical Infection Medicine, Faculty of Medicine, Lund University, Malmö, Sweden; Department of Infectious Diseases, Helsingborg Hospital, Helsingborg, Sweden.
    Lundgren, Maria
    Department of Clinical Immunology and Transfusion Medicine, Office of Medical Services, Lund, Sweden.
    Iliachenko, Elena
    Department of Clinical Immunology and Transfusion Medicine, Office of Medical Services, Lund, Sweden.
    Månsson, Fredrik
    Department of Translational Medicine, Clinical Infection Medicine, Faculty of Medicine, Lund University, Malmö, Sweden; Skåne University Hospital, Malmö, Sweden.
    Böttiger, Blenda
    Department of Clinical Microbiology, University and Regional Laboratories, Lund, Sweden.
    Landin-Olsson, Mona
    Skåne University Hospital, Malmö, Sweden; Department of Clinical Science, Division of Internal Medicine, Lund University, Lund, Sweden.
    Wikén, Christian
    Skåne University Hospital, Malmö, Sweden; Department of Clinical Sciences, Division of Infection Medicine, Lund University, Lund, Sweden.
    Rosendal, Ebba
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Wigren, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Kjeldsen-Kragh, Jens
    Department of Clinical Immunology and Transfusion Medicine, Office of Medical Services, Lund, Sweden.
    Rasmussen, Magnus
    Skåne University Hospital, Malmö, Sweden; Department of Clinical Sciences, Division of Infection Medicine, Lund University, Lund, Sweden.
    Kahn, Fredrik
    Skåne University Hospital, Malmö, Sweden; Department of Clinical Sciences, Division of Infection Medicine, Lund University, Lund, Sweden.
    Holm, Karin
    Skåne University Hospital, Malmö, Sweden; Department of Clinical Sciences, Division of Infection Medicine, Lund University, Lund, Sweden.
    Convalescent plasma treatment in severely immunosuppressed patients hospitalized with COVID-19: an observational study of 28 cases2022Inngår i: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 54, nr 4, s. 283-291Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Immunosuppressed patients are particularly vulnerable to severe infection from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), risking prolonged viremia and symptom duration. In this study we describe clinical and virological treatment outcomes in a heterogeneous group of patients with severe immunosuppression due to various causes suffering from COVID-19 infection, who were all treated with convalescent plasma (CCP) along with standard treatment.

    Methods: We performed an observational, retrospective case series between May 2020 to March 2021 at three sites in Skåne, Sweden, with a population of nearly 1.4 million people. All patients hospitalized for COVID-19 who received CCP with the indication severe immunosuppression as defined by the treating physician were included in the study (n = 28).

    Results: In total, 28 severely immunocompromised patients, half of which previously had been treated with rituximab, who had received in-hospital convalescent plasma treatment of COVID-19 were identified. One week after CCP treatment, 13 of 28 (46%) patients had improved clinically defined as a decrease of at least one point at the WHO-scale. Three patients had increased score points of whom two had died. For 12 patients, the WHO-scale was unchanged.

    Conclusion: As one of only few studies on CCP treatment of COVID-19 in hospitalized patients with severe immunosuppression, this study adds descriptive data. The study design prohibits conclusions on safety and efficacy, and the results should be interpreted with caution. Prospective, randomized trials are needed to investigate this further.

    Fulltekst (pdf)
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  • 27. Lozach, Pierre-Yves
    et al.
    Mancini, Roberta
    Bitto, David
    Meier, Roger
    Oestereich, Lisa
    Överby, Anna K
    Ludwig Institute for Cancer Research, Stockholm Branch, Karolinska Institute, Box 10 240, SE-17177 Stockholm, Sweden.
    Pettersson, Ralf F
    Helenius, Ari
    Entry of bunyaviruses into mammalian cells2010Inngår i: Cell host & microbe, ISSN 1934-6069, Vol. 7, nr 6, s. 488-499Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Bunyaviridae constitute a large family of enveloped animal viruses, many members of which cause serious diseases. However, early bunyavirus-host cell interactions and entry mechanisms remain largely uncharacterized. Investigating Uukuniemi virus, a bunyavirus of the genus Phlebovirus, we found that virus attachment to the cell surface was specific but inefficient, with 25% of bound viruses being endocytosed within 10 min, mainly via noncoated vesicles. The viruses entered Rab5a+ early endosomes and, subsequently, Rab7a+ and LAMP-1+ late endosomes. Acid-activated penetration, occurring 20-40 min after internalization, required maturation of early to late endosomes. The pH threshold for viral membrane fusion was 5.4, and entry was sensitive to temperatures below 25 degrees C. Together, our results indicate that Uukuniemi virus penetrates host cells by acid-activated membrane fusion from late endosomal compartments. This study also highlights the importance of the degradative branch of the endocytic pathway in facilitating entry of late-penetrating viruses.

  • 28. Lund, Harald
    et al.
    Pieber, Melanie
    Parsa, Roham
    Han, Jinming
    Grommisch, David
    Ewing, Ewoud
    Kular, Lara
    Needhamsen, Maria
    Espinosa, Alexander
    Nilsson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Butovsky, Oleg
    Jagodic, Maja
    Zhang, Xing-Mei
    Harris, Robert A.
    Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells2018Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 9, artikkel-id 4845Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Circulating monocytes can compete for virtually any tissue macrophage niche and become long-lived replacements that are phenotypically indistinguishable from their embryonic counterparts. As the factors regulating this process are incompletely understood, we studied niche competition in the brain by depleting microglia with >95% efficiency using Cx3cr1CreER/+R26DTA/+ mice and monitored long-term repopulation. Here we show that the microglial niche is repopulated within weeks by a combination of local proliferation of CX3CR1+F4/80lowClec12a microglia and infiltration of CX3CR1+F4/80hiClec12a+ macrophages that arise directly from Ly6Chi monocytes. This colonization is independent of blood brain barrier breakdown, paralleled by vascular activation, and regulated by type I interferon. Ly6Chi monocytes upregulate microglia gene expression and adopt microglia DNA methylation signatures, but retain a distinct gene signature from proliferating microglia, displaying altered surface marker expression, phagocytic capacity and cytokine production. Our results demonstrate that monocytes are imprinted by the CNS microenvironment but remain transcriptionally, epigenetically and functionally distinct.

    Fulltekst (pdf)
    fulltext
  • 29.
    Mihalič, Filip
    et al.
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, Uppsala, Sweden.
    Benz, Caroline
    Department of Chemistry - BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Kassa, Eszter
    Department of Chemistry - BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Lindquist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Simonetti, Leandro
    Department of Chemistry - BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Inturi, Raviteja
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, Uppsala, Sweden.
    Aronsson, Hanna
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, Uppsala, Sweden.
    Andersson, Eva
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, Uppsala, Sweden.
    Chi, Celestine N.
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, Uppsala, Sweden.
    Davey, Norman E.
    Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, United Kingdom.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Jemth, Per
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, Uppsala, Sweden.
    Ivarsson, Ylva
    Department of Chemistry - BMC, Uppsala University, Box 576, Husargatan 3, Uppsala, Sweden.
    Identification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets2023Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikkel-id 5636Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The virus life cycle depends on host-virus protein-protein interactions, which often involve a disordered protein region binding to a folded protein domain. Here, we used proteomic peptide phage display (ProP-PD) to identify peptides from the intrinsically disordered regions of the human proteome that bind to folded protein domains encoded by the SARS-CoV-2 genome. Eleven folded domains of SARS-CoV-2 proteins were found to bind 281 peptides from human proteins, and affinities of 31 interactions involving eight SARS-CoV-2 protein domains were determined (K D ∼ 7-300 μM). Key specificity residues of the peptides were established for six of the interactions. Two of the peptides, binding Nsp9 and Nsp16, respectively, inhibited viral replication. Our findings demonstrate how high-throughput peptide binding screens simultaneously identify potential host-virus interactions and peptides with antiviral properties. Furthermore, the high number of low-affinity interactions suggest that overexpression of viral proteins during infection may perturb multiple cellular pathways.

    Fulltekst (pdf)
    fulltext
  • 30.
    Mihalič, Filip
    et al.
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, 751 23, Uppsala, Sweden.
    Simonetti, Leandro
    Department of Chemistry - BMC, Uppsala University, Husargatan 3, Uppsala, Box 576, Sweden.
    Giudice, Girolamo
    European Molecular Biology Laboratory-European Bioinformatics Institute, Hinxton, United Kingdom.
    Sander, Marie Rubin
    Department of Pharmaceutical Biosciences, Uppsala University, Husargatan 3, Box 591, SE-751 24, Uppsala, Sweden.
    Lindquist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Peters, Marie Berit Akpiroro
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Benz, Caroline
    Department of Chemistry - BMC, Uppsala University, Husargatan 3, Uppsala, Box 576, Sweden.
    Kassa, Eszter
    Department of Chemistry - BMC, Uppsala University, Husargatan 3, Uppsala, Box 576, Sweden.
    Badgujar, Dilip
    Department of Chemistry - BMC, Uppsala University, Husargatan 3, Uppsala, Box 576, Sweden.
    Inturi, Raviteja
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, 751 23, Uppsala, Sweden.
    Ali, Muhammad
    Department of Chemistry - BMC, Uppsala University, Husargatan 3, Uppsala, Box 576, Sweden.
    Krystkowiak, Izabella
    Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London, United Kingdom.
    Sayadi, Ahmed
    Department of Chemistry - BMC, Uppsala University, Husargatan 3, Uppsala, Box 576, Sweden.
    Andersson, Eva
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, 751 23, Uppsala, Sweden.
    Aronsson, Hanna
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, 751 23, Uppsala, Sweden.
    Söderberg, Ola
    Department of Pharmaceutical Biosciences, Uppsala University, Husargatan 3, Box 591, SE-751 24, Uppsala, Sweden.
    Dobritzsch, Doreen
    Department of Chemistry - BMC, Uppsala University, Husargatan 3, Uppsala, Box 576, Sweden.
    Petsalaki, Evangelia
    European Molecular Biology Laboratory-European Bioinformatics Institute, Hinxton, United Kingdom.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Jemth, Per
    Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, 751 23, Uppsala, Sweden.
    Davey, Norman E.
    Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London, United Kingdom.
    Ivarsson, Ylva
    Department of Chemistry - BMC, Uppsala University, Husargatan 3, Uppsala, Box 576, Sweden.
    Large-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs2023Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikkel-id 2409Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Viruses mimic host short linear motifs (SLiMs) to hijack and deregulate cellular functions. Studies of motif-mediated interactions therefore provide insight into virus-host dependencies, and reveal targets for therapeutic intervention. Here, we describe the pan-viral discovery of 1712 SLiM-based virus-host interactions using a phage peptidome tiling the intrinsically disordered protein regions of 229 RNA viruses. We find mimicry of host SLiMs to be a ubiquitous viral strategy, reveal novel host proteins hijacked by viruses, and identify cellular pathways frequently deregulated by viral motif mimicry. Using structural and biophysical analyses, we show that viral mimicry-based interactions have similar binding strength and bound conformations as endogenous interactions. Finally, we establish polyadenylate-binding protein 1 as a potential target for broad-spectrum antiviral agent development. Our platform enables rapid discovery of mechanisms of viral interference and the identification of potential therapeutic targets which can aid in combating future epidemics and pandemics.

    Fulltekst (pdf)
    fulltext
  • 31.
    Panayiotou, Christakis
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Lindqvist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Kurhade, Chaitanya
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Vonderstein, Kirstin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Pasto, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Edlund, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Upadhyay, Arunkumar S.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Viperin restricts Zika virus and tick-borne encephalitis virus replication by targeting NS3 for proteasomal degradation2018Inngår i: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, nr 7, artikkel-id e02054-17Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Flaviviruses are arthropod-borne viruses that constitute a major global health problem, with millions of human infections annually. Their pathogenesis ranges from mild illness to severe manifestations such as hemorrhagic fever and fatal encephalitis. Type I interferons (IFNs) are induced in response to viral infection and stimulate the expression of interferon-stimulated genes (ISGs), including that encoding viperin (virus-inhibitory protein, endoplasmic reticulum associated, IFN inducible), which shows antiviral activity against a broad spectrum of viruses, including several flaviviruses. Here we describe a novel antiviral mechanism employed by viperin against two prominent flaviviruses, tick-borne encephalitis virus (TBEV) and Zika virus (ZIKV). Viperin was found to interact and colocalize with the structural proteins premembrane (prM) and envelope (E) of TBEV, as well as with nonstructural (NS) proteins NS2A, NS2B, and NS3. Interestingly, viperin expression reduced the NS3 protein level, and the stability of the other interacting viral proteins, but only in the presence of NS3. We also found that although viperin interacted with NS3 of mosquito-borne flaviviruses (ZIKV, Japanese encephalitis virus, and yellow fever virus), only ZIKV was sensitive to the antiviral effect of viperin. This sensitivity correlated with viperin's ability to induce proteasome-dependent degradation of NS3. ZIKV and TBEV replication was rescued completely when NS3 was overexpressed, suggesting that the viral NS3 is the specific target of viperin. In summary, we present here a novel antiviral mechanism of viperin that is selective for specific viruses in the genus Flavivirus, affording the possible availability of new drug targets that can be used for therapeutic intervention.

    IMPORTANCE Flaviviruses are a group of enveloped RNA viruses that cause severe diseases in humans and animals worldwide, but no antiviral treatment is yet available. Viperin, a host protein produced in response to infection, effectively restricts the replication of several flaviviruses, but the exact molecular mechanisms have not been elucidated. Here we have identified a novel mechanism employed by viperin to inhibit the replication of two flaviviruses: tick-borne encephalitis virus (TBEV) and Zika virus (ZIKV). Viperin induced selective degradation via the proteasome of TBEV and ZIKV non-structural 3 (NS3) protein, which is involved in several steps of the viral life cycle. Furthermore, viperin also reduced the stability of several other viral proteins in a NS3-dependent manner, suggesting a central role of NS3 in viperin's antiflavivirus activity. Taking the results together, our work shows important similarities and differences among the members of the genus Flavivirus and could lead to the possibility of therapeutic intervention.

  • 32.
    Persson, B. David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Nord, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Lindquist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Danskog, Katarina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (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 universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Arnberg, Niklas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    BAF45b is required for efficient zika virus infection of HAP1 cells2021Inngår i: Viruses, E-ISSN 1999-4915, Vol. 13, nr 10, artikkel-id 2007Artikkel i tidsskrift (Fagfellevurdert)
    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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  • 33. Peña Cárcamo, José R.
    et al.
    Morell, María L.
    Vázquez, Cecilia A.
    Vatansever, Sezen
    Upadhyay, Arunkumar S.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Cordo, Sandra M.
    García, Cybele C.
    The interplay between viperin antiviral activity, lipid droplets and Junín mammarenavirus multiplication2018Inngår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 514, s. 216-229Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Junín arenavirus infections are associated with high levels of interferons in both severe and fatal cases. Upon Junín virus (JUNV) infection a cell signaling cascade initiates, that ultimately attempts to limit viral replication and prevent infection progression through the expression of host antiviral proteins. The interferon stimulated gene (ISG) viperin has drawn our attention as it has been highlighted as an important antiviral protein against several viral infections. The studies of the mechanistic actions of viperin have described important functional domains relating its antiviral and immune-modulating actions through cellular lipid structures. In line with this, through silencing and overexpression approaches, we have identified viperin as an antiviral ISG against JUNV. In addition, we found that lipid droplet structures are modulated during JUNV infection, suggesting its relevance for proper virus multiplication. Furthermore, our confocal microscopy images, bioinformatics and functional results also revealed viperin-JUNV protein interactions that might be participating in this antiviral pathway at lipid droplet level. Altogether, these results will help to better understand the factors mediating innate immunity in arenavirus infection and may lead to the development of pharmacological agents that can boost their effectiveness thereby leading to new treatments for this viral disease.

  • 34.
    Pulkkinen, Lauri I. A.
    et al.
    Faculty of Biological and Environmental Sciences, Molecular and Integrative Bioscience Research Programme, University of Helsinki, Helsinki, Finland; Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Barrass, Sarah V.
    Faculty of Biological and Environmental Sciences, Molecular and Integrative Bioscience Research Programme, University of Helsinki, Helsinki, Finland; Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Domanska, Aušra
    Faculty of Biological and Environmental Sciences, Molecular and Integrative Bioscience Research Programme, University of Helsinki, Helsinki, Finland; Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Anastasina, Maria
    Faculty of Biological and Environmental Sciences, Molecular and Integrative Bioscience Research Programme, University of Helsinki, Helsinki, Finland; Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Butcher, Sarah J.
    Faculty of Biological and Environmental Sciences, Molecular