Targeted delivery of flagellin by nebulization offers optimized respiratory immunity and defense against pneumococcal pneumonia

Novel therapeutic approaches for addressing pneumonia caused by Streptococcus pneumoniae, which exhibit resistance to standard-of-care antibiotics are greatly needed. One viable approach involves precisely stimulating innate immune defenses within the lungs. Using murine models of pneumococcal pneumonia, prior studies demonstrated that intranasal administration of the Toll-like receptor 5 agonist, flagellin, results in a 100-fold decrease in lung infection compared to sole antibiotic therapy, when used as an adjunct treatment to the antibiotic. To promote the transfer of this immunotherapy to clinics and mitigate unwanted systemic inflammation, this project assessed whether the direct delivery of flagellin to the airways through nebulization stimulates respiratory defenses against bacterial infection. Similarly to intranasal administration, nebulized flagellin induced a transient activation of lung innate immunity. In contrast, inhalation by nebulization resulted in an attenuated activation of systemic immune responses. We conclude that flagellin aerosol therapy represents a secure and promising approach in addressing bacterial pneumonia within the context of antimicrobial resistance.