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Regulation of flagellum biosynthesis in response to cell envelope stress in Salmonella Typhimurium

ABSTRACT: Flagella-driven motility of Salmonella enterica serovar Typhimurium facilitates host colonization. However, the large extracellular flagellum is also a prime target for the immune system. As consequence, expression of flagella is bistable within a population of Salmonella, resulting in flagellated and non-flagellated subpopulations. This allows the bacteria to maximize fitness in hostile environments. The degenerate EAL-domain protein RflP (formerly YdiV) is responsible for the bistable expression of flagella by directing the flagellar master regulatory complex FlhD4C2 to proteolytic degradation. The environmental cues controlling expression of rflP and thus the bistable flagellar biosynthesis remain ambiguous. Here, we demonstrate that RflP responds to cell envelope stress and alterations of outer membrane integrity. Lipopolysaccharide (LPS) truncation mutants of Salmonella Typhimurium exhibited increasing motility defects due to downregulation of flagellar gene expression. Transposon mutagenesis and genetic profiling revealed that σ24 (RpoE) and Rcs phosphorelay-dependent cell envelope stress response systems sense modifications of lipopolysaccharide, low pH activity of the complement system. This subsequently results in activation of RflP expression and degradation of FlhD4C2 via ClpXP. We speculate that diverse hostile environments inside the host might result in cell envelope damage and would thus trigger the repression of resource-costly and immunogenic flagella biosynthesis via activation of the cell envelope stress response.

ORGANISM(S): Salmonella enterica subsp. enterica serovar Typhimurium str. LT2

PROVIDER: GSE87447 | GEO | 2018/04/13

REPOSITORIES: GEO

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Project description:Background: Salmonella enterica serovar Typhimurium (S. Typhimurium) is a Gram-negative pathogen that must successfully adapt to the broad fluctuations in the concentration of dissolved dioxygen encountered in the host. In Escherichia coli, ArcA (Aerobic Respiratory Control) helps the cells to sense and respond to the presence of dioxygen. The global role of ArcA in E. coli is well characterized; however, little is known about its role in anaerobically grown S. Typhimurium. Results: We compared the transcriptional profiles of the virulent wild-type (WT) strain (ATCC 14028s) and its isogenic arcA mutant grown under anaerobic conditions. We found that ArcA directly or indirectly regulates 392 genes (8.5% of the genome); of these, 138 genes are poorly characterized. Regulation by ArcA in S. Typhimurium is similar, but distinct from that in E. coli. Thus, genes/operons involved in core metabolic pathways (e.g., succinyl-CoA, fatty acid degradation, cytochrome oxidase complexes, flagellar biosynthesis, motility, and chemotaxis) were regulated similarly in the two organisms. However, genes/operons present in both organisms, but regulated differently by ArcA in S. Typhimurium included those coding for ethanolamine utilization, lactate transport and metabolism, and succinate dehydrogenases. Salmonella-specific genes/operons regulated by ArcA included those required for propanediol utilization, flagellar genes (mcpAC, cheV), Gifsy-1 prophage genes, and a few SPI-3 genes (mgtBC, slsA, STM3784). In agreement with our microarray data, the arcA mutant was non-motile, lacked flagella, and was as virulent in mice as the WT. Furthermore, we identified a set of 120 genes whose regulation was shared with the anaerobic redox regulator, Fnr. Conclusion(s): We have identified the ArcA regulon in anaerobically grown S. Typhimurium. Our results demonstrated that in S. Typhimurium, ArcA serves as a transcriptional regulator coordinating cellular metabolism, flagella biosynthesis, and motility. Furthermore, ArcA and Fnr share in the regulation of 120 S. Typhimurium genes.

Project description:Salmonella Typhimurium is an enteric food-borne pathogen responsible for causing salmonellosis associated with acute diarrhea. The bacterial invasion initially requires flagellar motility to reach the intestinal lumen and to cross the mucus layer of the intestinal epithelia and subsequent adhesion to the host cell, mainly mediated by fimbriae .The key genes involved in the pathogenic process are encoded within highly conserved regions of the bacterial genome called Salmonella Pathogenicity Islands (SPIs). The key regulator HilA, which is positively regulated by HilC and HilD, is located in SPI-1;however, other virulence-related regulators, such as RtsA, are encoded outside this island . During the invasion, proteins encoded by the prgHIJK, spaMNOPQRS, and invABCEFGH SPI-1 operons constitute a Type-3 Secretion System. Effector proteins,such as SipA and SipC (encoded in SPI-1) and SigD/SopB (encoded in SPI-5), translocate to the host cytosol through this system causing intracellular changes and inducing the immune response . The survival and replication of intracellular Salmonella inside Salmonella-containing vacuoles (SCVs) is mainly mediated by the genes located in SPI-2. The immune response is activated through the recognition of pathogen-associated molecular patterns (PAMPs) by specific receptors expressed on the surface and/or inside different cell types. The most important PAMPs are flagellin (monomers comprising the flagella filaments), particularly the FliC subunit, which is highly expressed on the bacterial surface, and lipopolysaccharide (LPS).Oxygen availability is limited in the inflamed gut whereas other compounds, such as hydrogen sulfide (H2S) and H2 are abundantly produced by the colonic bacteria. In addition, nutrients are also limited inside the SCV, while reactive oxygen as wellas nitrogen species may be found . In anaerobic conditions, Salmonella is able to survive by using alternative energy sources, such as nitrate or fumarate, through the use of specific enzymes: nitrate and nitrite reductases, fumarate reductase , DMSO reductase and respiratory hydrogenases.In a previous study, we compared transcriptomes of a clinical isolate of S. Typhimurium (strain 50-wt) and its derivative-multidrug-resistant mutant (strain 50-64) using microarrays . In addition to showing antimicrobial resistance, strain was also less invasive. In the present study, we focused on the genes of unknown function that showed impaired expression. We further selected those genes with a putative role in the acquired resistance phenotype or in the observed repressed virulence observed. Here, 4 putative membrane proteins and the yedF of unknown function were investigated to evaluate their involvement inthese two phenotypes.

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Regulation of flagellum biosynthesis in response to cell envelope stress in Salmonella Typhimurium

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