Commensal Neisseria Modulates Host IL-6 to Promote Oral Colonization

Abstract

Abstract Neisseria musculi, isolated from the oral cavity of wild caught mice, weakly (50%) colonizes C57BL/6J (B6) mice but readily colonizes CAST/EiJ (CAST) mice. In vitro stimulation of B6 or CAST splenocytes with WT Neisseria or E. coli LPS showed that CAST mice had a blunted inflammatory response producing significantly lower levels of IL-6 than B6 mice. The use of specific genetic knockouts highlighted a need for an intact innate immune system to prevent colonization. B6-RAG-1−/− were colonized at a similar rate to WT B6 while B6-MyD88−/− and TLR4−/− mice were readily colonized like CAST (100%). In vitro stimulation of B6 BMDM or splenocytes with WT Neisseria yielded only low levels of IL-6. A series of Neisseria mutants in the Type IV Pilus (TFP), a key component of bacterial-host interaction, failed to colonize susceptible CAST mice and showed increased levels of IL-6 compared to WT Neisseria stimulation, indicating that the TFP plays a role in down regulating host IL-6 production. Surprisingly, UV-inactivated Neisseria induced high levels of IL-6 regardless of TFP status supporting that this is an active bacterial process and the presence of TFP alone was unable to down regulate IL-6 production. Consistent with a critical role for IL-6 is preventing colonization, mice deficient for the IL-6 receptor were colonized at a rate of 100% indicating host IL-6 signaling plays a critical role in determining host colonization susceptibility.