Respiratory infections with pneumococci establish multi-pronged heterotypic protection against pneumonia
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Acute lower respiratory tract infections are a persistent and pervasive public health burden, often caused by Streptococcus pneumoniae. Hospitalization rates due to pneumonia fall dramatically during early childhood, remain low during early adult years, and then increase steadily around middle age. The low-susceptibility period of early adulthood is likely due to frequent respiratory exposures to diverse pneumococcal serotypes resulting in serotype-independent heterotypic immunity. We hypothesize that resolution of repeated respiratory pneumococcal infections establish capsule-independent, lung-resident adaptive immunity that protects against subsequent unrelated pneumococcal pneumonia. In our model of naturally acquired heterotypic immunity, mice are infected with diverse serotypes of pneumococci in the respiratory tract, given time to recover, and then challenged by pulmonary infection with a highly virulent serotype 3 pneumococcus (Sp3). Prior exposures to unrelated pneumococci resulted in multi-log reductions in Sp3 bacterial lung burdens and long-term sterilizing immunity. The enhanced lung defense during pneumonia included more Th17 cells in the lung and significantly elevated IL-17A as well as neutrophils in the airspaces. Depletion of CD4+ cells resulted in less effective antibacterial defense. Upon ex vivo stimulation with pneumococcus lung-resident CD4+ cells produced multiple protective cytokines including IL-17A, IFN-γ, IL-22, IL-2, and TNF-α. In protected lungs, there were increased numbers of CD4+ resident memory T (TRM) cells, confined to the anatomic region of the initial infections. Heterotypic protection was also confined to the site of previous pneumococcal infections. Previously-exposed mice challenged in their contralateral lobes were not protected. RNAseq analysis of heterotypic lungs 24h after Sp3 infection revealed an enrichment of lymphocyte-related pathways including immunoglobulin and other B cell-related genes. B cell-deficient µMT-/- mice exposed to pneumococci had intermediate protection against Sp3 pneumonia, better than naïve mice but less effective than fully immunocompetent peers. Plasma from mice previously exposed to pneumococci was sufficient to protect naïve mice against Sp3 pneumonia. We conclude that mechanisms of naturally-acquired heterotypic protection against pneumococcus involve both lung-resident cell-mediated and humoral immunity and importantly this protection can be compartmentalized within the lung. Advancing our understanding of these mechanisms will guide future vaccine development and treatment strategies for lung disease.