The Critical Role of Type I Interferons in Murine Hepatitis Virus Proliferation and Liver Pathology 9168

Abstract Description Type I Interferons (IFN-I) are crucial in restricting the proliferation and pathology of the murine hepatitis virus (MHV). Macrophages in the liver highly express the MHV receptor, CEACAM-1, thus we were interested in understanding how macrophages mediate the antiviral effects of IFN-I during MHV infection. So, wildtype (WT) and IFNAR-/- C57BL/6 mice were infected with MHV-A58 via i.p., intranasal, and oral routes. Compared to WT mice, IFNAR-/- mice developed an acute infection and hepatitis within 3 days following i.p. injection of MHV-A58, while they were less susceptible to intranasal and oral routes of administration. The susceptibility was dependent on peritoneal macrophages, as their depletion in IFNAR-/- mice completely prevented acute liver pathology and significantly reduced viral load in both the serum and liver. Peritoneal macrophages in IFNAR-/-mice were depleted using Clodronate liposomes, followed by intraperitoneal administration of MHV. Cytokine array analysis revealed reduced inflammatory response cytokine profiles in both the serum and liver of macrophage-depleted IFNAR-/- mice, similar to those observed in WT mice. In vitro apoptosis studies using poly I:C stimulation showed that macrophages from IFNAR-/- mice exhibit greater resistance to apoptosis and viral replication. These findings clearly show Type I IFN signalling is crucial in preventing liver pathology against MHV through controlling MHV replication and regulating macrophage apoptosis. Funding Sources CIHR Topic Categories Viral Immunology (VIR)