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Type I interferon shapes brain distribution and tropism of tick-borne flavivirus
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand.ORCID iD: 0000-0003-3214-6605
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).ORCID iD: 0000-0001-8512-0535
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).ORCID iD: 0000-0003-3445-7829
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. 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. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).ORCID iD: 0000-0002-2993-8647
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 2007Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer Nature , 2023. Vol. 14, no 1, article id 2007
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-206780DOI: 10.1038/s41467-023-37698-0ISI: 000967732600009PubMedID: 37037810Scopus ID: 2-s2.0-85152115180OAI: oai:DiVA.org:umu-206780DiVA, id: diva2:1752758
Funder
The Kempe Foundations, SMK-1532Knut and Alice Wallenberg Foundation, KAW2015.0284Swedish Research Council, 2018-05851Swedish Research Council, 2017-01307Swedish Research Council, 2020-06224Swedish Research Council, 2021-06602Available from: 2023-04-24 Created: 2023-04-24 Last updated: 2023-09-05Bibliographically approved
In thesis
1. Host-pathogen interactions during tick-borne flavivirus infection: pathogenesis, tropism and tools
Open this publication in new window or tab >>Host-pathogen interactions during tick-borne flavivirus infection: pathogenesis, tropism and tools
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Värd-patogen-interaktioner vid fästingburen flavivirus infektion : patogenes, tropism och verktyg
Abstract [en]

Tick-borne encephalitis virus (TBEV) is a neurotropic member of the genus Flavivirus. It may transmit to humans through the bite of an infected tick or consumption of unpasteurized dairyproducts, and causes tick-borne encephalitis (TBE). TBE constitutes a significant health burden in Eurasia, with more than 10,000 cases reported every year. In this thesis, I have investigated the role of the innate immune response in restricting infection in the central nervous system (CNS), identified virulence factors and developed a new model system to study the structural proteins of TBEV.

Viral tropism is important for understanding underlying mechanisms of pathology. In the first part,we combined whole-brain imaging with single nuclei RNA-sequencing after infection of wildtype (WT) and interferon (IFN) α/β receptor knockout (Ifnar-/-) mice by Langat virus (LGTV), a low-virulent model for TBEV. We found that absence of type I IFN signaling changes viral tropism and leads to an impaired inflammatory response. For neurons, astrocytes, and microglia we also compared the response to LGTV infection in vivo with the response of primary monocultures infected in vitro. Primary cells are often used for mechanistic studies of neurotropic viruses, but we found limited overlap in altered pathways between in vivo and in vitro, which emphasizes the role of cellular crosstalk in shaping the transcriptional response to infection in the brain.

The second part addresses viral determinants of pathogenicity. By comparing disease progression induced by different TBEV strains in a mouse model, we identified TBEV 93/783 as a highly virulentstrain belonging to the European subtype. We could show that two unusual amino acid substitutions in the envelope (E) protein of 93/783 enhanced neurovirulence and contributed to pathogenesis. To facilitate further studies of the structural proteins of TBEV, we generated and thoroughlycharacterized a chimeric virus with the pre-membrane (prM) and ecto-E protein of TBEV 93/783 in the genetic background of LGTV. The chimeric virus shows similar growth kinetics as the parental LGTV in vitro but is less pathogenic in our mouse model. Meanwhile, it remained neurovirulent and structurally similar to TBEV, making it a useful tool for studying the structural proteins of TBEV under lower biosafety conditions. Taken together, these findings deepen our understanding of what determines the outcome of tick-borne flavivirus infection and the utility of the available model systems for studying disease mechanisms. 

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2023. p. 61
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2244
Keywords
Tick-borne encephalitis virus, Langat virus, pathogenesis, type I interferons, central nervous system, neuroinflammation, structural proteins
National Category
Microbiology in the medical area Infectious Medicine
Research subject
Infectious Diseases; Microbiology
Identifiers
urn:nbn:se:umu:diva-207013 (URN)978-91-8070-072-6 (ISBN)978-91-8070-071-9 (ISBN)
Public defence
2023-05-26, Sal B, 9 tr., Tandläkarhögskolan, Norrlands universitetssjukhus, Umeå, 13:00 (English)
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Supervisors
Available from: 2023-04-28 Created: 2023-04-25 Last updated: 2023-04-26Bibliographically approved

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Chotiwan, NunyaRosendal, EbbaWillekens, Stefanie M. A.Schexnaydre, ErinNilsson, EmmaLindquist, RichardHahn, MaxMihai, Ionut SebastianZhang, JianguoCarlson, Lars-AndersHenriksson, JohanAhlgren, UlfMarcellino, DanielÖverby, Anna K.

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Chotiwan, NunyaRosendal, EbbaWillekens, Stefanie M. A.Schexnaydre, ErinNilsson, EmmaLindquist, RichardHahn, MaxMihai, Ionut SebastianMorini, FedericoZhang, JianguoCarlson, Lars-AndersHenriksson, JohanAhlgren, UlfMarcellino, DanielÖverby, Anna K.
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Department of Clinical MicrobiologyMolecular Infection Medicine Sweden (MIMS)Umeå Centre for Molecular Medicine (UCMM)Wallenberg Centre for Molecular Medicine at Umeå University (WCMM)Department of Medical Biochemistry and BiophysicsUmeå Centre for Microbial Research (UCMR)Department of Molecular Biology (Faculty of Medicine)Department of Integrative Medical Biology (IMB)
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Nature Communications
Microbiology in the medical areaMedical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)Neurosciences

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