Innate immune and inflammatory responses to coronaviruses

Coronavirus infection of both human and mice can result in severe disease, characterized by significant immunopathology that is spurred by an exuberant, yet dysregulated, innate immune response with a poor adaptive immune response. Disease pathology is exacerbated by the host immune response in the respiratory tract and Central Nervous System (CNS), resulting in morbidity and mortality. One mechanism by which coronaviruses generate dysregulated immune responses is by encoding innate immune antagonist genes. One such gene is a conserved accessory gene within the +1 Open Reading Frame (ORF) of nucleocapsid called the internal N gene. This gene is referred to as “I” for mouse hepatitis virus (MHV), ORF9b for severe acute respiratory CoV (SARS-CoV-) and SARS-CoV-2, and ORF8b for Middle East respiratory syndrome CoV (MERS-CoV). In this thesis I describe a mild innate immune antagonist function for the MHV-JHM strain internal N protein “I”. I show genetic deletion of JHMV I resulted in a highly attenuated virus both in vitro and in vivo that displayed a post RNA replication/transcription defect that ultimately resulted in fewer infectious virions packaged compared to wild type virus. This is unique to JHM as another MHV virus, A59, did not display the same phenotypes and highlights a previously unappreciated role for CoV accessory proteins.