Abstract

NF-{kappa}B driven cellular immunity is essential for both pro- and anti-inflammatory responses to microbes, which makes it one of the most frequently targeted pathways by bacteria during pathogenesis. How NF-{kappa}B tunes the epithelial response to Streptococcus pneumoniae across the spectrum of commensal to pathogenic outcomes is not fully understood. In this study, we compare a commensal-like 6B ST90 strain to an invasive TIGR4 isolate and demonstrate that TIGR4 both blunts and antagonizes NF-{kappa}B activation. We identified, through comparative mass spectrometry of the p65 interactome, that the 6B ST90 isolate drives a non-canonical NF-{kappa}B RelB cascade, whereas TIGR4 induces p65 degradation though aggrephagy. Mechanistically, TIGR4 challenge triggers a novel interaction of COMMD2 with p65 and p62. This complex mediates export of p65 for degradation and is necessary for repressing host inflammatory transcription. With these results, we reveal for the first time a new bacterial pathogenesis mechanism to repress host inflammatory response though COMMD2 mediated turnover of p65, and present a paradigm for diverging NF-{kappa}B responses to pneumococcus.