Cd302 and Cr1l restrict human hepatotropic virus cross-species transmission to mice [2Ectopic expression]

Virus species- and tissue-tropism is governed by host dependency and restriction factors. Hepatitis C virus (HCV) exhibits a narrow species-tropism and murine hepatocytes are refractory to infection. Using murine liver cDNA library screening we identified Cd302, a lectin, and Cr1l, a complement receptor, as pan-genotypic restrictors of HCV infection. Cd302/Cr1l interact to impede virion uptake and co-operatively induce a non-canonical transcriptional program, inhibiting HCV and hepatitis B virus (HBV) infection in vitro. CAS9 disruption of murine hepatocyte Cd302 expression increased HCV permissiveness in-vivo and ex-vivo, and modulated the intrinsic hepatocyte transcriptome dysregulating metabolic process and host defense genes. In contrast, co-operative CD302/CR1L expression was absent and HCV restriction reduced in human hepatocytes. The Cd302/Cr1l axis therefore contributes to limiting hepatotropic virus cross-species transmission to mice, opening new avenues for step-wise development of mouse models for these important human pathogens, which cause substantial disease burden globally. Overall design: Huh-7.5 cell-lines stably overexpressing the indicated murine gene(s) were used for infection experiments. To determine whether the over expression of murine genes modulated the intrinsic transcriptome of these x4 over-expressing cell-lines, 3 different passages of each cell-line were taken. RNA was extracted and used for RNA-seq.