Viral pneumonias remain a global health threat necessitating novel strategies to prevent and treat these lower respiratory tract infections. We have reported that mice treated with a combination of inhaled Toll-like receptor (TLR) 2/6 and TLR 9 agonists (Pam2-ODN) are broadly protected against respiratory pathogens. Although a single inhalation of Pam-ODN prevents acute morbidity and chronic complications associated with viral pneumonias, the mechanisms underlying this protection remain incompletely elucidated. Here, we show in a lethal paramyxovirus model that Pam2-ODN-enhanced survival is associated with robust virus inactivation that occurs prior to internalization by lung epithelial cells. However, it was also noted that viral mortality in sham-treated mice temporally corresponded with CD8+ T cell-enriched lung inflammation that peaks after the viral burden wanes. Pam2-ODN treatment also blocked this injurious inflammation, but the attenuation of lymphocytic inflammation and the reduction in virus burden were both lost when inducible reactive oxygen species generation was inhibited. Depleting CD8+ T cells before or after viral challenge underscored the balanced roles of CD8+ T cells in antiviral immunity and fatal immunopathology, but did not obviate the Pam2-ODN antiviral protection. These findings identify multifunctional inducible antiviral mechanisms and may reveal means to protect susceptible individuals against respiratory infections.

Inducible epithelial resistance improves survival of Sendai virus pneumonia in mice by both inactivating virus and preventing CD8+ T cell-mediated immunopathology