Type I interferons prevent cell death and liver immunopathology in Mouse Hepatitis Virus infected mice 2333173

Abstract Introduction Type I interferons (IFNs) hinder the viral replication process and regulate the immune system to mount an antiviral response. However, there is little research on how type I IFNs can prevent virally induced immunopathology. The mouse hepatitis virus (MHV) is a highly contagious murine pathogen that exhibits broad cellular tropism and leads to a plethora of symptoms, including fulminant hepatitis. Despite being a mouse-specific pathogen, using MHV as a model can help us understand the development of immunopathology in the absence of type I IFN signalling. Methods Type I IFN receptor knockout (IFNAR-/-) and wild-type (WT) C57BL/6 mice were infected with MHV-A58 through oral gavage and intraperitoneal injections. Serum and liver homogenates were used for measuring viral titres and cytokine array analyses. Disulfiram was administered intraperitoneally to inhibit pyroptosis. Liver lobes were sent for histology to study the immunopathology of the disease. Results IFNAR-/- mice were highly susceptible to MHV infection compared to WT mice, experiencing lethal immunopathology in the liver, a cytokine storm, and significantly higher viral titres. Liver histology of infected IFNAR-/- mice exhibited high levels of hemorrhaging and necrosis. This data suggested that type I IFN signalling was not only critical for stemming the spread of the infection but also for preventing the development of lethal immunopathology. To elucidate the mechanism, we studied their role in cell death pathways in hepatocytes. Inhibition of pyroptosis led to decreased liver immunopathology and inflammation with no effect on the viral titres. This suggested that type I IFNs can prevent pyroptosis to limit liver immunopathology during MHV infections. Conclusion Research on how type I IFNs can regulate and prevent the development of lethal immunopathology is critical for advancing therapeutic strategies against hyperinflammatory disease during viral infection. Funding Source Canadian Institutes of Health Research Topic Categories Viral Immunology (VIR)