Control of Hepatitis C Virus Replication in Mouse Liver-Derived Cells by MAVS-Dependent Production of Type I and Type III Interferons

Abstract

Hepatitis C virus (HCV) efficiently infects IMPORTANCEIn this study, we found that HCV NS3-4A similarly diminished both human and mouse MAVS-dependent signaling in human and mouse cells. Therefore, it is unlikely that ineffective cleavage of mouse MAVS per se precludes HCV propagation in immunocompetent mouse liver cells. Hence, approaches to reinforce HCV replication in mouse liver cells (e.g., by expression of essential human replication cofactors) should not be thwarted by the poor ability of HCV to counteract MAVS-dependent antiviral signaling. In addition, we show that mouse MAVS induces both type I and type III IFNs, which together control HCV replication. Characterization of type I or type III-dependent interferon-stimulated genes in these cells should help to identify key murine restriction factors that preclude HCV propagation in immunocompetent mouse liver cells. H epatitis C virus (HCV) infection is associated with chronic liver disease, including hepatic steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (1). Recent licensing of directly acting antivirals (DAAs) has considerably improved therapeutic options, and novel drug combinations reach cure rates of more than 90% (2). However, natural or treatment-induced virus elimination does not prevent reinfection by HCV. Moreover, many of ca. 160 million infected individuals are not diagnosed, and the vast majority of HCV patients have not been treated (3). Therefore, development of a prophylactic vaccine that efficiently prevents virus transmission is a major challenge for global control of hepatitis C. However, advances in HCV vaccine research are hampered by a lack HCV-permissive, immunocompetent animal models.HCV, a plus-strand RNA virus and member of the family Flaviviridae, has a narrow species tropism. Besides humans, only chimpanzees are naturally susceptible to chronic HCV infection. However, high costs and ethical concerns severely limit utilization of chimpanzees for research purposes. Thus, understanding of the mechanisms that limit HCV replication in other animals, for instance, mice, is an important step to ultimately develop a robust animal model for HCV. Encouragingly, recent advances have highlighted key prerequisites for HCV infection of murine liver cells. First, occludin and CD81 have been recognized to determine HCV species tropism at the level of viral cell entry (4). Importantly, this blockade can be overcome by engineering mice to express human occludin and CD81 (5) or by adaptation of HCV to usage of mouse CD81 (6). Second, HCV replication in murine embryonic fibroblasts (7,8), in mouse liver-derived cells (9), and

Guarding the frontiers: the biology of type III interferons

“…Mouse liver shows no expression of IFNλR1 and no responsiveness to IFN-λ in vivo 22,23 , but liver cells derived from mice require the IFNλR1 receptor for efficient control of viral replication 24 . In humans, mucosal epithelial tissues as well as the liver respond to type III IFNs 25,26 .…”

MAVS Coordination of Antiviral Innate Immunity

“…This hypothesis that differential localization of MAVS drives different antiviral signaling programs is an attractive one. Indeed, MAVS does signal to induce both type I and type III IFNs in response to virus infection, including hepatitis C virus (HCV) (15,16). However, MAVS signaling is likely more complicated than differential localization simply regulating differential activation of transcriptional responses.…”

“…While specific peroxisomal cleavage of MAVS by NS3-NS4A has not been tested, the finding that a portion of NS3-NS4A is localized to peroxisomes suggests that it could cleave peroxisomal MAVS. Indeed, NS3-NS4A does block antiviral induction of both type I and type III IFNs (16,20). Why would the HCV NS3-NS4A protease cleave MAVS on the MAM but not the mitochondria?…”

Duck Tembusu Virus Nonstructural Protein 1 Antagonizes IFN-β Signaling Pathways by Targeting VISA

“…Considering the critical role of VISA in innate antiviral signaling, it is not surprising that viruses adopted various strategies to evade immunity by targeting VISA. For example, NS3/4A of hepatitis C virus and GB viruses cleaves human and mouse VISA to reduce signaling transduction (28,58). The 3C pro cysteine protease of Coxsackie virus B3 cleaves VISA as a mechanism to escape host immunity (59).…”