Critical role of innate immunity to flagellin in absence of adaptive immunity.

Zou, Jun; Zhao, Xu; Shi, Zhenda; Zhang, Zhan; Vijay-Kumar, Matam; Chassaing, Benoit; Gewirtz, Andrew T

BACKGROUND Bacterial flagellin is a major target of innate and adaptive immunity, both of which can promote and/or compensate for deficiencies in each other's function. AIM/METHODS To investigate the role of innate immune detection of flagellin irrespective of adaptive immunity, we examined the consequences of loss of toll-like receptor 5 (T5) and/or Nod-like receptor 4 (N4) upon a Rag1-deficient background. RESULTS Mice lacking TLR5 and Rag1 (T5/Rag-DKO) exhibited frequent lethal Pasteurellaceae-containing abscesses that prevented breeding of these mice. Mice lacking TLR5, NLRC4, and Rag1 (T5/N4/Rag-TKO) also resulted in sporadic lethal abdominal abscesses caused by similar Pasteurellaceae. In the absence of such infections, relative to Rag1-KO, T5/N4/Rag-TKO mice exhibited microbiota encroachment, low-grade inflammation, microbiota dysbiosis, and, moreover were highly prone to Citrobacter infection and developed severe colitis when adoptively transferred with colitogenic T-cells. Relative proneness of T5/N4/Rag-TKO mice to T-cell colitis was ablated by antibiotics while fecal microbiota transplant from T5/N4/Rag-TKO mice to WT mice transferred proneness to Citrobacter infection, indicating that dysbiosis in T5/N4/Rag-TKO mice contributed to these phenotypes. CONCLUSIONS These results demonstrate a critical role for innate immune detection of flagellin, especially in the intestinal tract and particularly in hosts deficient in adaptive immunity.