Innate immune detection of flagellin positively and negatively regulates Salmonella infection. (P4001)

Abstract

Abstract Salmonella enterica Typhimurium is a flagellated bacterium and one of the leading causes of gastroenteritis in humans. Bacterial flagellin is critical for motility and also a prime target of the innate immune system. Innate immune recognition of flagellin is mediated by at least two independent pathways, TLR5 and Naip5-Naip6/NlrC4/Caspase-1. The functional significance of each of the two independent flagellin recognition systems in innate immunity to wild type Salmonella infection is complex, and contribute to both protection and susceptibility. We hypothesized that this was due to efficient modulation of flagellin expression in vivo and evasion of innate immune detection. Salmonella deficient in the anti-sigma factor flgM overexpress flagellin, are attenuated in vivo, and this attenuation is dependent on flagellin expression. In this study, we used flgM- Salmonella to determine if flagellin recognition by the innate immune system is responsible for the attenuation of flgM- S. typhimurium, and to dissect the contribution of each flagellin recognition pathway to bacterial clearance, inflammation and infection. We demonstrate that caspase-1 controls systemic infection of flgM- S. Typhimurium, and also limits intestinal inflammation and injury. In contrast, TLR5 paradoxically promotes bacterial colonization in the cecum, and attenuates intestinal inflammation. Our results indicate that Salmonella evasion of caspase-1 dependent flagellin recognition is critical for establishing systemic infection and that evasion of TLR5 and caspase-1 dependent flagellin recognition help Salmonella induce intestinal inflammation and establish a niche in the inflamed gut.