A double edge function of type 17 immunity in Streptococcus pneumoniae pathogenesis during a co-infection with Influenza A Virus

Abstract

Abstract Streptococcus pneumoniae (Spn) is a respiratory pathogen responsible for significant global disease burden (otitis media, pneumonia, sepsis). Despite success with current Pneumococcal Conjugate Vaccines, a significant proportion of humans remain colonized with Spn, rendering them at risk for developing Spn infections. Upper respiratory nasopharyngeal (NP) colonization by Spn is a precursor to disease, and viral induced inflammation is a key risk factor for the transition of commensal colonization to disease pathogenesis. We utilized a mouse co-infection model of Spn and influenza virus to determine the role of virus induced acute inflammation in the transition of Spn colonization to disease pathogenesis. We show that early Spn NP colonization is allowed by an immune quiescence state, maintained by the lack of IL-17 expression. Introduction of influenza virus in Spn colonized mice elicits a robust IL-17 driven inflammatory response, which induces robust neutrophilia and tissue damage in the NP. The IL-17 mediated inflammatory response was associated with a significant increase in Spn NP bacterial density, leading to Spn invasion and bacteremia. Antibody mediated neutralization of IL-17 suppressed NP inflammation and bacterial density and prevented bacteremia. IL-17 receptor expression was also detected in nasal myeloid cell infiltrate. RoRγt-KO mice remained protected from bacteremia, mimicking the reduced pathogenesis of IL-17 neutralized WT mice. Using RoRγtGFP mutant mice, we detected the recruitment of GFP expressing RoRγt cell population in NP lavages and nasal associated lymphoid tissues. We conclude that IL-17 blockade could contain influenza induced NP pathology and protect against Spn invasive pathogenesis.