Immune pathways that regulate neutrophil activation and replenishment prevent persistent pneumococcal colonization

Here, we examine immune signaling pathways affecting the duration of primary nasopharyngeal colonization by <i>Streptococcus pneumoniae</i> (<i>Spn</i>), the first step in its pathogenesis. <i>Spn</i> colonization which lasts days to weeks in WT mice was persistent (≥ 6 months) in the absence of IL-17RA-signaling. RNA-seq analysis confirmed the role of IL-17RA signaling in neutrophil-associated pathways. Rather than driving neutrophil specific chemokine expression, IL-17RA-signaling was required to replenish neutrophils in nasal tissue that were otherwise depleted during infection. Enhanced neutrophil trafficking correlated with IL-17RA-dependent expression of endothelial cell adhesion molecules that promote neutrophil trafficking from the circulation into nasal tissue. Persistent colonization was also observed in mice lacking IL-1R-signaling. Recognition of IL-1-family cytokines, however, was not necessary for the expression of IL-17A or neutrophil recruitment. Instead, IL-1R-signaling was associated with the activation of neutrophils in nasal tissue that displayed increased levels of the surface marker CD11b, an important receptor for the complement-opsonized phagocytosis of <i>Spn</i>. Our findings provide insight into the requirement for sustained neutrophil presence and activity to prevent persistent mucosal infection by a leading opportunistic mucosal pathogen.