Source-specific priming of lung NK cells by Pseudomonas LPS enhances resistance to bacterial pneumonia

Bacterial pneumonia is a major cause of morbidity and mortality in elderly individuals, yet how mucosal innate immunity changes with age remains unclear. We detected bacterial DNA, particularly signatures of Pseudomonas, in the circulation of healthy elderly individuals, suggesting that chronic exposure to low-dose microbial components occurs during aging. Using murine models, we found that intratracheal delivery of a low dose of Pseudomonas aeruginosa lipopolysaccharide (LPS) strongly protected against bacterial pneumonia through a microbiota-dependent mechanism, whereas Escherichia coli LPS had no detectable protective effect. This protective response occurred in the absence of adaptive immunity and was mediated by lung-resident natural killer (NK) cells. Transcriptomic profiling revealed that P. aeruginosa LPS selectively upregulated the complement receptor C3aR1 in pulmonary NK cells, increasing their IFN-γ production and LFA-1-dependent adhesion to target cells. Adoptive transfer of P. aeruginosa LPS-conditioned pulmonary NK cells conferred protection to naïve recipients, whereas silencing C3aR1 abrogated this effect. This localized innate training occurred without systemic inflammation and required the presence of a commensal microbiota. These findings reveal that structurally distinct LPS from P. aeruginosa programs lung NK cells toward a C3aR1-driven, high-affinity effector state that enhances resistance to bacterial pneumonia. Source-specific innate conditioning of mucosal NK cells may provide a tissue-targeted strategy to strengthen pulmonary host defense, particularly in aging populations vulnerable to respiratory infections.