Defining parameters that influence susceptibility and protection to murine respiratory beta-coronavirus MHV-1 infection

Abstract

Abstract Patients infected with SARS-CoV-2 can experience variable susceptibility and sepsis-like immune dysfunction. Also, patients with comorbidities such as previous septic events are more likely to be hospitalized and succumb to COVID19 complications. However, the extent to which respiratory beta-coronavirus pathology is dose dependent and produces sepsis-like dysregulation in an experimental murine model are not completely defined. We utilized an established SARS-like murine model by infecting Murine Hepatitis Virus 1 (MHV-1) susceptible C3H/HeJ mice intranasally and analyzed responses over time after primary and/or secondary challenges. Immunologically naïve C3H mice undergo pathological changes defined by dose-dependent changes in disease severity and lung infiltrate/edema. MHV-infected mice also experience sepsis-like lymphopenia and cytokine dysregulation in the blood. Importantly, a low/surviving dose (5×10 2PFU) was identified that yielded no morbidity/mortality after infection of C3H hosts. However, this low dose provides antibody dependent but not CD4/CD8 circulatory T cell dependent protection against a lethal high dose MHV-1 re-challenge. In addition, while C3H hosts with history of prior infections were more resistant, C3H mice that survived surgical sepsis showed increased susceptibility to MHV-1 infection over their surgical sham controls. Together, these data define how infection dose, immunological status, and/or comorbidities influence outcome of primary and secondary beta-coronavirus infections in highly susceptible hosts. Supported by grants from NIH (R35GM134880, T32AI007511)