Myeloid cell reprogramming drives enhanced defense against Streptococcus pneumoniae lung infection following exposure to commensal Prevotella.

Clinical data link the prevalent respiratory tract anaerobe Prevotella with reduced pneumonia mortality, but the mechanisms directing Prevotella regulation of lung immune homeostasis are unclear. Here, single-cell RNA sequencing was employed to define the transcriptional immune signatures underlying improved clearance of Streptococcus pneumoniae following lung exposure to Prevotella melaninogenica. Overall, we observed a substantial shift in myeloid cell transcriptional programming from interferon-dominant to a more antibacterial profile in S. pneumoniae-infected mice after pre-exposure to P. melaninogenica, correlating with increased macrophage and neutrophil phagocytosis of S. pneumoniae and improved pathogen clearance. In neutrophils, tumor necrosis factor (TNF) signaling through TNFR2 was essential for increased antimicrobial function. Moreover, improved defense required CCR2-dependent monocyte-derived macrophages, with selective enrichment of more a mature Cxcl3+ population which was distinct from the hallmark S. pneumoniae-associated C1qa+ population enriched in the absence of effective clearance. Together, these findings inform the myeloid cell transcriptional changes associated with natural infection resistance mediated by pulmonary microbial exposures.