Inducible epithelial resistance promotes survival of viral pneumonia by inactivating virus particles and preventing CD8+ T cell dependent immunopathology

Abstract

Abstract Respiratory viral infections cause significant morbidity and mortality worldwide, necessitating the development of novel strategies to prevent complications of respiratory infections. Our group has discovered the phenomenon of inducible epithelial resistance where mice treated with combination inhalation of Toll-like receptor (TLR) 2/6 and TLR9 agonists (Pam2-ODN) are protected against respiratory pathogens, including viruses. We investigated the mouse survival benefits of paramyxovirus, Sendai (SeV) infection and found that Pam2-ODN treatment one day prior to SeV challenge enhanced survival of mice. This protection was associated with reduced CD8+ T cell inflammation. Depletion of CD8+T cells prior to infection increased baseline virus susceptibility but did not affect protection afforded by Pam2-ODN. Depletion of CD8+T cells after viral burden waned but before peak mortality enhanced SeV pneumonia survival, even in the absence of Pam2-ODN pretreatment, revealing the profound role of CD8+ T cell mediated immunopathology in virus-induced mortality. We further demonstrated that Pam2-ODN treatment controls viral replication by inactivation of SeV prior to epithelial internalization. Epithelial generation of reactive oxygen species induced by Pam2-ODN treatment is necessary for SeV inactivation and preventing CD8+T cell mediated immunopathology. These findings highlight antiviral mechanisms of inducible epithelial resistance and may provide means to protect vulnerable immunocompromised patients against respiratory diseases.