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Liver-expressed Cd302 and Cr1l limit hepatitis C virus cross-species transmission to mice

Author(s): Brown, Richard JP; Tegtmeyer, Birthe; Sheldon, Julie; Khera, Tanvi; Anggakusuma; et al

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Abstract: Hepatitis C virus (HCV) has no animal reservoir, infecting only humans. To investigate species barrier determinants limiting infection of rodents, murine liver complementary DNA library screening was performed, identifying transmembrane proteins Cd302 and Cr1l as potent restrictors of HCV propagation. Combined ectopic expression in human hepatoma cells impeded HCV uptake and cooperatively mediated transcriptional dysregulation of a noncanonical program of immunity genes. Murine hepatocyte expression of both factors was constitutive and not interferon inducible, while differences in liver expression and the ability to restrict HCV were observed between the murine orthologs and their human counterparts. Genetic ablation of endogenous <i>Cd302</i> expression in human HCV entry factor transgenic mice increased hepatocyte permissiveness for an adapted HCV strain and dysregulated expression of metabolic process and host defense genes. These findings highlight human-mouse differences in liver-intrinsic antiviral immunity and facilitate the development of next-generation murine models for preclinical testing of HCV vaccine candidates.
Publication Date: 4-Nov-2020
Citation: Brown, Richard JP, Tegtmeyer, Birthe, Sheldon, Julie, Khera, Tanvi, Anggakusuma, Todt, Daniel, Vieyres, Gabrielle, Weller, Romy, Joecks, Sebastian, Zhang, Yudi, Sake, Svenja, Bankwitz, Dorothea, Welsch, Kathrin, Ginkel, Corinne, Engelmann, Michael, Gerold, Gisa, Steinmann, Eike, Yuan, Qinggong, Ott, Michael, Vondran, Florian WR, Krey, Thomas, Ströh, Luisa J, Miskey, Csaba, Ivics, Zoltán, Herder, Vanessa, Baumgärtner, Wolfgang, Lauber, Chris, Seifert, Michael, Tarr, Alexander W, McClure, C Patrick, Randall, Glenn, Baktash, Yasmine, Ploss, Alexander, Thi, Viet Loan Dao, Michailidis, Eleftherios, Saeed, Mohsan, Verhoye, Lieven, Meuleman, Philip, Goedecke, Natascha, Wirth, Dagmar, Rice, Charles M, Pietschmann, Thomas. (2020). Liver-expressed <i>Cd302</i> and <i>Cr1l</i> limit hepatitis C virus cross-species transmission to mice.. Science advances, 6 (45), 10.1126/sciadv.abd3233
DOI: doi:10.1126/sciadv.abd3233
ISSN: 2375-2548
EISSN: 2375-2548
Pages: eabd3233 - eabd3233
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: Science Advances
Version: Final published version. This is an open access article.

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