Abstract
ABSTRACTSalmonella enterica serovar Typhimurium can cross the epithelial barrier using either the invasion-associated type III secretion system (T3SS-1) or a T3SS-1-independent mechanism that remains poorly characterized. Here we show that flagellum-mediated motility supported a T3SS-1-independent pathway for entering ileal Peyer’s patches in the mouse model. Flagellum-dependent invasion of Peyer’s patches required energy taxis toward nitrate, which was mediated by the methyl-accepting chemotaxis protein (MCP) Tsr. Generation of nitrate in the intestinal lumen required inducible nitric oxide synthase (iNOS), which was synthesized constitutively in the mucosa of the terminal ileum but not in the jejunum, duodenum, or cecum. Tsr-mediated invasion of ileal Peyer’s patches was abrogated in mice deficient for Nos2, the gene encoding iNOS. We conclude that Tsr-mediated energy taxis enables S. Typhimurium to migrate toward the intestinal epithelium by sensing host-derived nitrate, thereby contributing to invasion of Peyer’s patches.
Highlights
Salmonella enterica serovar Typhimurium can cross the epithelial barrier using either the invasion-associated type III secretion system (T3SS-1) or a T3SS-1-independent mechanism that remains poorly characterized
Modeling of epithelial invasion in the 1980s using cultured epithelial cell lines identified flagellum-mediated motility [4] and the invasion-associated type III secretion system (T3SS-1) [5] encoded by Salmonella pathogenicity island 1 (SPI1) [6] as potential virulence factors contributing to epithelial entry
We reasoned that if flagella and T3SS-1 contribute to the same invasion pathway, the invasion defect observed for an invA fliC fljB mutant should be similar to that of an invA mutant, because the mutation in invA would epistatically mask the phenotype caused by mutations in fliC and fljB
Summary
Salmonella enterica serovar Typhimurium can cross the epithelial barrier using either the invasion-associated type III secretion system (T3SS-1) or a T3SS-1-independent mechanism that remains poorly characterized. We observed that flagellum-mediated motility and chemotaxis contributed to a T3SS-1-independent pathway for invasion and systemic dissemination to the spleen This pathway required the methyl-accepting chemotaxis protein (MCP) Tsr and energy taxis toward hostderived nitrate, which we found to be generated by inducible nitric oxide synthase (iNOS) in the ileal mucosa prior to infection. An initial characterization of these potential virulence factors in the mouse typhoid model suggested that inactivation of flagellum biosynthesis genes causes less attenuation (2- to 9-fold) [7] than inactivation of T3SS-1 biosynthesis genes (16- to 60-fold) [5, 8, 9] This early work helped erect the concept that T3SS-1 represents the main virulence factor for mucosal invasion, while flagella are not a major contributor to Salmonella pathogenesis.
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