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 Streptococcus pneumoniae (Spn), the first step in its pathogenesis. Spn 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. The onset of clearance required neutrophils, but there was no detectable increase in their numbers. 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 Spn. Colonization of dual-knockout mice showed the contributions of IL-1 and IL-17 signaling pathways were non-redundant. Expression of the chemokine Cxcl5 was impaired in the absence of either IL-1R or IL-17RA signaling, suggesting a role in both activation and maintenance of the neutrophil population during infection. Our findings provide insight into the requirement for sustained neutrophil presence and activity to prevent persistent mucosal infection by a leading opportunistic mucosal pathogen.