Effects of immunoproteasome inhibition on acute respiratory infection with murine hepatitis virus strain 1.

The immunoproteasome (IP) is a predominantly inducible component of the ubiquitin proteasome system that plays key roles in multiple aspects of immune function, inflammation, and protein homeostasis. We used murine hepatitis virus strain 1 (MHV-1), a mouse coronavirus, to define the role of IP activity during acute coronavirus respiratory infection. Expression of the β5i subunit of the IP and cytokines that induce IP activity, including IFN-γ, TNF-α, and IFN-β, increased in lungs and livers of CH3/HeJ mice following intranasal infection with MHV-1. IP inhibition using ONX-0914 did not affect MHV-1 replication in bone marrow-derived dendritic cells IMPORTANCE: Inflammatory responses triggered by acute infection by respiratory viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drive morbidity and mortality. Infection of mice with murine hepatitis virus strain 1 (MHV-1), a mouse coronavirus, is a useful model to study the pathogenesis of coronavirus respiratory infections. The immunoproteasome is an inducible component of the ubiquitin proteasome system that is poised to contribute to multiple aspects of immune function, inflammation, and protein homeostasis during an infection. We used the MHV-1 model to define the role of the immunoproteasome in coronavirus pathogenesis. We found that immunoproteasome subunit expression increases in the lungs and the liver during acute MHV-1 respiratory infection. Inhibition of immunoproteasome activity did not affect MHV-1 replication but increased MHV-1-induced weight loss, mortality, and inflammation in lungs and livers. Thus, our findings indicate that the immunoproteasome is a critical protective host factor during coronavirus respiratory infection.