B7 Family Molecule VSIG4 Regulates Intestinal Anti-Enterohemorrhagic Escherichia coli Immunity by Altering Gut Flora Diversity.
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ABSTRACT:
SUBMITTER: He Z
PROVIDER: S-EPMC8398431 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To better understand the role of host cell-derived molecules on enterohemorrhagic Escherichia coli (EHEC) infection, we studied EHEC virulence gene expression when exposed to cell-free spent (conditioned) medium (CM) from HCT-8 intestinal epithelial cells. Exposure to HCT-8 CM for 1 h and 3 h increased the expression of 32 of 41 EHEC locus of enterocyte effacement (LEE) virulence genes compared with fresh medium (FM). Expression of the Shiga toxin 1 (stx1B) gene was up-regulated at 1 h of exposure. Seventeen genes encoded by prophage 933W, including those for Stx2, were also up-regulated at both time-points. The increase in 933W prophage expression was mirrored by a 2.7-fold increase in phage titers. Consistent with the increase in virulence gene expression, we observed a fivefold increase in EHEC attachment to epithelial cells when exposed to CM. The increase in EHEC attachment was abolished when CM was heated to 95 °C or treated with proteinase K to degrade the proteins. The host cell-derived molecule(s) were larger than 3 kDa, which suggests that the molecule(s) that increase EHEC virulence and attachment are protein-based.
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Project description:Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is an important foodborne pathogen causing severe diseases in humans worldwide. Currently, there is no specific treatment available for EHEC infection and the use of conventional antibiotics is contraindicated. Therefore, identification of potential therapeutic targets and development of effective measures to control and treat EHEC infection are needed. Lipopolysaccharides (LPS) are surface glycolipids found on the outer membrane of gram-negative bacteria, including EHEC, and LPS biosynthesis has long been considered as potential anti-bacterial target. Here, we demonstrated that the EHEC rfaD gene that functions in the biosynthesis of the LPS inner core is required for the intestinal colonization and pathogenesis of EHEC in vivo. Disruption of the EHEC rfaD confers attenuated toxicity in Caenorhabditis elegans and less bacterial colonization in the intestine of C. elegans and mouse. Moreover, rfaD is also involved in the control of susceptibility of EHEC to antimicrobial peptides and host intestinal immunity. It is worth noting that rfaD mutation did not interfere with the growth kinetics when compared to the wild-type EHEC cells. Taken together, we demonstrated that mutations of the EHEC rfaD confer hypersusceptibility to host intestinal innate immunity in vivo, and suggested that targeting the RfaD or the core LPS synthesis pathway may provide alternative therapeutic regimens for EHEC infection.
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Project description:The large intestinal pathogen enterohemorrhagic Escherichia coli (EHEC) O157:H7 detects host cues to regulate virulence gene expression during colonization and infection. However, virulence regulatory mechanisms of EHEC O157:H7 in the human large intestine are not fully understood. Herein, we identified a virulence-regulating pathway where the PhoQ/PhoP two-component regulatory system senses low magnesium levels and signals to the O island 119-encoded Z4267 (LmiA; low magnesium-induced regulator A), directly activating loci of enterocyte effacement genes to promote EHEC O157:H7 adherence in the large intestine. Disruption of this pathway significantly decreased EHEC O157:H7 adherence in the mouse intestinal tract. Moreover, feeding mice a magnesium-rich diet significantly reduced EHEC O157:H7 adherence in vivo This LmiA-mediated virulence regulatory pathway is also conserved among several EHEC and enteropathogenic E. coli serotypes; therefore, our findings support the use of magnesium as a dietary supplement and provide greater insights into the dietary cues that can prevent enteric infections.IMPORTANCE Sensing specific gut metabolites is an important strategy for inducing crucial virulence programs by enterohemorrhagic Escherichia coli (EHEC) O157:H7 during colonization and infection. Here, we identified a virulence-regulating pathway wherein the PhoQ/PhoP two-component regulatory system signals to the O island 119-encoded low magnesium-induced regulator A (LmiA), which, in turn, activates locus of enterocyte effacement (LEE) genes to promote EHEC O157:H7 adherence in the low-magnesium conditions of the large intestine. This regulatory pathway is widely present in a range of EHEC and enteropathogenic E. coli (EPEC) serotypes. Disruption of this pathway significantly decreased EHEC O157:H7 adherence in the mouse intestinal tract. Moreover, mice fed a magnesium-rich diet showed significantly reduced EHEC O157:H7 adherence in vivo, indicating that magnesium may help in preventing EHEC and EPEC infection in humans.
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Project description:Enterohemorrhagic Escherichia coli (EHEC) is a food-borne pathogen that causes diarrheal disease and the potentially lethal hemolytic uremic syndrome. We used an infant rabbit model of EHEC infection that recapitulates many aspects of human intestinal disease to comprehensively assess colonic transcriptional responses to this pathogen. Cellular compartment-specific RNA-sequencing of intestinal tissue from animals infected with EHEC strains containing or lacking Shiga toxins (Stx) revealed that EHEC infection elicits a robust response that is dramatically shaped by Stx, particularly in epithelial cells. Many of the differences in the transcriptional responses elicited by these strains were in genes involved in immune signaling pathways, such as IL23A, and coagulation, including F3, the gene encoding Tissue Factor. RNA FISH confirmed that these elevated transcripts were found almost exclusively in epithelial cells. Collectively, these findings suggest that Stx potently remodels the host innate immune response to EHEC.
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Project description:Enterohemorrhagic Escherichia coli (EHEC) 0157:H7 is a food-borne pathogen that can cause bloody diarrhea and, occasionally, acute renal failure as a consequence of Shiga toxin (Stx) production by the organism. Stxs are potent cytotoxins that are lethal to animals at low doses. Thus, Stxs not only harm the host but, as reported here, also significantly enhance the capacity of EHEC O157:H7 to adhere to epithelial cells and to colonize the intestines of mice. Tissue culture experiments showed that this toxin-mediated increase in bacterial adherence correlated with an Stx-evoked increase in a eukaryotic receptor for the EHEC O157:H7 attachment factor intimin.
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Project description:The present study aimed to investigate the molecular mechanisms, including potential genes, pathways and interactions, underlying the effect of intestinal flora on intestinal health. The gene expression profiles of GSE22648 were downloaded from the Gene Expression Omnibus database to screen differentially expressed genes (DEGs). The Database for Annotation, Visualization and Integrated Discovery was used for Gene Ontology (GO) functional and pathway enrichment analysis of the DEGs. DEG‑associated literature was mined using the GenCLip 2.0 online tool. Finally, GO and pathway enrichment analyses of the DEGs in the literature were processed. By comparing microbiota‑depleted mouse samples and control mouse samples, a total of 115 DEGs, including 58 upregulated genes and 57 downregulated genes, were screened. The upregulated genes were enriched into various GO terms, including microsome, oxidation reduction and heme binding, whereas the 57 downregulated DEGs were enriched in different functions, including DNA packaging and linoleic acid metabolism. A total of 19 genes, including baculoviral IAP repeat containing 5, aurora kinase A, angiotensin I converting enzyme 2 and free fatty acid receptor 2 were identified and enriched in four modules, including cell division, chromosome segregation, inflammatory bowel disease and inflammatory response. AURKA, inner centromere protein antigens 135/155 kDa, baculoviral IAP repeat containing 5, aurora kinase B and solute carrier family 22 (organic cation/zwitterion transporter) member 4 were identified as potential important genes for intestinal flora and intestinal disease treatment through their involvement in various functions, including cell division, chromosome segregation, inflammatory bowel disease and inflammatory response.
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Project description:T cell activation by APCs is positively and negatively regulated by members of the B7 family. We have identified a previously unknown function for B7 family-related protein V-set and Ig domain-containing 4 (VSIG4). In vitro experiments using VSIG4-Ig fusion molecules showed that VSIG4 is a strong negative regulator of murine and human T cell proliferation and IL-2 production. Administration to mice of soluble VSIG4-Ig fusion molecules reduced the induction of T cell responses in vivo and inhibited the production of Th cell-dependent IgG responses. Unlike that of B7 family members, surface expression of VSIG4 was restricted to resting tissue macrophages and absent upon activation by LPS or in autoimmune inflammatory foci. The specific expression of VSIG4 on resting macrophages in tissue suggests that this inhibitory ligand may be important for the maintenance of T cell unresponsiveness in healthy tissues.
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Project description:Enterohemorrhagic Escherichia coli (EHEC) O157:H7 causes hemorrhagic colitis and hemolytic uremic syndrome (HUS) by colonizing the gut mucosa and producing Shiga toxins (Stx). The only factor clearly demonstrated to play a role in EHEC adherence to intestinal epithelial cells is intimin, which binds host cell integrins and nucleolin, as well as a receptor (Tir) that it injects into the host cell. Here we report that EHEC O157:H7 produces adhesive type IV pili, which we term hemorrhagic coli pilus (HCP), composed of a 19-kDa pilin subunit (HcpA) that is encoded by the hcpA chromosomal gene. HCP were observed as bundles of fibers greater than 10 microm in length that formed physical bridges between bacteria adhering to human and bovine host cells. Sera of HUS patients, but not healthy individuals, recognized HcpA, suggesting that the pili are produced in vivo during EHEC infections. Inactivation of the hcpA gene in EHEC EDL933 resulted in significantly reduced adherence to cultured human intestinal and bovine renal epithelial cells and to porcine and bovine gut explants. An escN mutant, which is unable to translocate Tir, adhered less than the hcpA mutant, suggesting that adherence mediated by intimin-Tir interactions is a prelude to HCP-mediated adherence. An hcpA and stx1,2 triple mutant and an hcpA mutant had similar levels of adherence to bovine and human epithelial cells while a stx1,2 double mutant had only a minor defect in adherence, indicating that HCP-mediated adherence and cytotoxicity are independent events. Our data establish that EHEC O157:H7 HCP are intestinal colonization factors that are likely to contribute to the pathogenic potential of this food-borne pathogen.
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