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 two independent innate immune pathways, TLR5 and Naip5-Naip6/NlrC4/Caspase-1. The functional significance of each of the two independent flagellin recognition systems in innate immunity to Salmonella infection is modest, and we hypothesized that this was due to efficient modulation of flagellin expression in vivo to evade 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 was responsible for the attenuation of flgM- S. typhimurium, and to dissect the contribution of each flagellin recognition pathway to bacterial clearance, inflammation and infection. Our results indicate that Salmonella evasion of caspase-1 dependent flagellin recognition is critical for establishing systemic infection and inducing intestinal inflammation and injury during intestinal infection. In contrast, TLR5 paradoxically promotes bacterial colonization in the cecum, but does not influence systemic infection, and plays a modest role in intestinal inflammation.
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