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

Abstract

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 in vitro. IP inhibition in vivo exacerbated virus-induced weight loss and mortality but had no effect on virus replication in lungs or livers. IP inhibition had minimal effect on virus-induced pulmonary inflammation but led to substantially increased liver pathology, including greater upregulation of pro-inflammatory cytokines and histological evidence of inflammation and necrosis. Those findings were associated with evidence of increased endoplasmic reticulum stress although not with accumulation of ubiquitinated protein. Our results indicate that the IP is a protective host factor during acute MHV-1 infection.

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.