title: Innate immune detection of flagellin positively and negatively regulates salmonella infection.
abstract: Salmonella enterica serovar Typhimurium is a flagellated bacterium and one of the leading causes of gastroenteritis in humans. Bacterial flagellin is required 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 for host defense against wild type Salmonella infection is complex, and innate immune detection of flagellin contributes to both protection and susceptibility. We hypothesized that efficient modulation of flagellin expression in vivo permits Salmonella to evade innate immune detection and limit the functional role of flagellin-specific host innate defenses. To test this hypothesis, we used Salmonella deficient in the anti-sigma factor flgM, which overproduce flagella and are attenuated in vivo. In this study we demonstrate that flagellin recognition by the innate immune system is responsible for the attenuation of flgM(-) S. Typhimurium, and dissect the contribution of each flagellin recognition pathway to bacterial clearance and inflammation. We demonstrate that caspase-1 controls mucosal and systemic infection of flgM(-) S. Typhimurium, and also limits intestinal inflammation and injury. In contrast, TLR5 paradoxically promotes bacterial colonization in the cecum and systemic infection, but attenuates intestinal inflammation. Our results indicate that Salmonella evasion of caspase-1 dependent flagellin recognition is critical for establishing infection and that evasion of TLR5 and caspase-1 dependent flagellin recognition helps Salmonella induce intestinal inflammation and establish a niche in the inflamed gut.
authors: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors: Marvin A
authors: MA
authors: Lai
authors: Ellen K
authors: EK
authors: Quarles
authors: Américo H
authors: AH
authors: López-Yglesias
authors: Xiaodan
authors: X
authors: Zhao
authors: Adeline M
authors: AM
authors: Hajjar
authors: Kelly D
authors: KD
authors: Smith
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D020170:Caspase 1 / Q000378:metabolism*; D002432:Cecum / Q000378:metabolism / Q000382:microbiology; D002478:Cells, Cultured; D005408:Flagellin / Q000276:immunology*; D005759:Gastroenteritis / Q000276:immunology / Q000382:microbiology; D015870:Gene Expression / Q000276:immunology; D057131:Immune Evasion; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000382:microbiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012480:Salmonella Infections / Q000276:immunology* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000276:immunology*; D013307:Streptomycin / Q000494:pharmacology; D051198:Toll-Like Receptor 5 / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D051198:Toll-Like Receptor 5; D005408:Flagellin; D020170:Caspase 1; D013307:Streptomycin
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