Viral pneumonia remains a global health threat despite worldwide vaccination and therapeutic programs. The influenza pandemic of 1918 and SARS-CoV2 pandemic of 2019-2020 are cautionary reminders demanding the need for novel treatment strategies. Moreover, in addition to causing acute disease, respiratory virus infections are often complicated by chronic lung pathologies, such as asthma induction, progression, and exacerbation. We have reported that mice treated with a combination of inhaled Toll-like receptor (TLR) 2/6 and TLR 9 agonists (Pam2-ODN) to stimulate innate immunity are broadly protected against respiratory pathogens, but 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 by reactive oxygen species (ROS), which occurs prior to internalization by lung epithelial cells. We also found that mortality in sham-treated mice temporally corresponded with CD8+ T cell-enriched lung inflammation that peaks on days 11-12 after viral challenge, when the viral burden has waned to a scarcely detectable level. Pam2-ODN treatment blocked this injurious inflammation by reducing the viral burden. Alternatively, depleting CD8+ T cells 8 days after viral challenge also decreased mortality. Notably, Pam2-ODN treatment of mice lacking CD8+ T cells at any point of SeV infection showed a similar degree of protection demonstrating Pam2-ODN mediated protection independent of CD8+ T cell response. Further, Pam2-ODN treatment protected SeV challenged mice from progressing to asthma-like disease by initiating acute anti-viral effects. Interestingly, mice aerosolized with Pam2-ODN after viral clearance displayed reduced eosinophilia that was associated with reduced lung epithelial IL-33 production. Findings from this study reveal opportunities for targeted immunomodulation to protect susceptible individuals from mortality of respiratory virus infections and preventing progression to chronic asthma
