Abstract
ABSTRACTViral pneumonias cause profound worldwide morbidity, necessitating novel strategies to prevent and treat these potentially lethal infections. Stimulation of intrinsic lung defenses via inhalation of synergistically acting Toll-like receptor (TLR) agonists protects mice broadly against pneumonia, including otherwise-lethal viral infections, providing a potential opportunity to mitigate infectious threats. As intact lung epithelial TLR signaling is required for the inducible resistance and as these cells are the principal targets of many respiratory viruses, the capacity of lung epithelial cells to be therapeutically manipulated to function as autonomous antiviral effectors was investigated. Our work revealed that mouse and human lung epithelial cells could be stimulated to generate robust antiviral responses that both reduce viral burden and enhance survival of isolated cells and intact animals. The antiviral protection required concurrent induction of epithelial reactive oxygen species (ROS) from both mitochondrial and dual oxidase sources, although neither type I interferon enrichment nor type I interferon signaling was required for the inducible protection. Taken together, these findings establish the sufficiency of lung epithelial cells to generate therapeutically inducible antiviral responses, reveal novel antiviral roles for ROS, provide mechanistic insights into inducible resistance, and may provide an opportunity to protect patients from viral pneumonia during periods of peak vulnerability.
Highlights
Viral pneumonias cause profound worldwide morbidity, necessitating novel strategies to prevent and treat these potentially lethal infections
Inducible protection against bacterial and fungal infections uniformly correlates with reductions in lung pathogen burden [12,13,14, 17, 18], the Pam2-ODN effect on lung viral burdens has not been assessed
The Pam2-ODNinduced lung viral burden differential continues to increase to the time of peak mortality, and inoculum titration studies (Fig. S1B) indicate that viral reductions of the magnitude observed in these studies are sufficient to afford profound survival increases
Summary
Viral pneumonias cause profound worldwide morbidity, necessitating novel strategies to prevent and treat these potentially lethal infections. The antiviral protection required concurrent induction of epithelial reactive oxygen species (ROS) from both mitochondrial and dual oxidase sources, neither type I interferon enrichment nor type I interferon signaling was required for the inducible protection Taken together, these findings establish the sufficiency of lung epithelial cells to generate therapeutically inducible antiviral responses, reveal novel antiviral roles for ROS, provide mechanistic insights into inducible resistance, and may provide an opportunity to protect patients from viral pneumonia during periods of peak vulnerability. We have reported that the lung’s mucosal defenses can be stimulated to protect mice against a wide array of otherwise lethal pneumonias, including those caused by influenza A viruses [10,11,12,13,14] This inducible resistance is achieved following a single inhaled treatment comprised of a synergistic combination of Toll-like receptor (TLR) agonists: a diacylated lipopeptide ligand for TLR2/6, Pam2CSK4, and a class C unmethylated 2=-deoxyribocytidine-phosphate-guanosine (CpG) ligand for TLR9, ODN M362 (here, Pam2-ODN) [10, 13,14,15]. We postulated that generating antiviral responses directly from the principal target of many respiratory viruses—the respiratory epithelium [16]— could be a highly efficacious strategy to reduce virus-induced host pathology
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