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

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 Cd302 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.

Three-Dimensional Cell Culture Systems for Studying Hepatitis C Virus

“…However, it is required for HCV to recruit clathrin components for endocytosis. Moreover, Brown et al [ 30 ] used the organoid system to characterize the role of two transmembrane proteins, Cd302 and Cr1l, in HCV infection. They are species barriers restricting HCV replication in rodents.…”

Improved Functionality of Exhausted Intrahepatic CXCR5+ CD8+ T Cells Contributes to Chronic Antigen Clearance Upon Immunomodulation

“…However, experimental models that mimic the unique immunological characteristics upon HBV and HCV infection as well as the development of late stage liver diseases, would greatly facilitate our understanding of CXCR5+ CD8+ T cells for the treatment of infected patients. Of note, recent emerging strategies eliminating mouse-specific HCV restriction factors ( 19 ) might pave the way towards the development of such models.…”

“…A deeper understanding of exhausted T cells in chronic liver infection is hindered by the lack of an appropriate infection model that recapitulates HBV and HCV infection. While overexpression of human specific entry factors ( 18 ) and elimination of mouse restriction factors ( 19 ) recently facilitated HCV infection in mice, it remains to be elucidated if these models can also reflect late infection states, i.e., the establishment of chronic infections and corresponding/accompanying diseases such as liver fibrosis, cirrhosis and eventually liver failure.…”

Initial HCV infection of adult hepatocytes triggers a temporally structured transcriptional program containing diverse pro- and anti-viral elements

“…Of note, significant targeting of multiple pathways associated with nuclear receptor (NR) signaling was detected in both PHHs and Huh-7.5 cells, further confirming that Huh-7.5 cells retain some HCV-inducible programs that are of biological relevance. NR-mediated signaling regulates transcriptional programs that control host metabolic processes and lipid metabolism and are reported to modulate susceptibility to HCV infection in both humans (37) and mice (38). (7).…”