Intestinal antimicrobial peptides during homeostasis, infection, and disease

Muniz, Luciana R.; Knosp, Camille; Yeretssian, Garabet

doi:10.3389/fimmu.2012.00310

Cited by 186 publications

(162 citation statements)

References 195 publications

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“…Within the small intestine, numerous antimicrobial peptides are constitutively produced by Paneth cells and are concentrated in the mucus covering the mucosa (64)(65)(66). One response of the mucosa to proinflammatory cytokines released as a result of Salmonella infection is to increase the production of defensins (67). Polymorphonuclear cells also contain numerous classes of antimicrobial peptides within cytoplasmic granules (68,69).…”

Section: Figmentioning

confidence: 99%

Novel Determinants of Intestinal Colonization of Salmonella enterica Serotype Typhimurium Identified in Bovine Enteric Infection

et al. 2013

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Cattle are naturally infected with Salmonella enterica serotype Typhimurium and exhibit pathological features of enteric salmonellosis that closely resemble those in humans. Cattle are the most relevant model of gastrointestinal disease resulting from nontyphoidal Salmonella infection in an animal with an intact microbiota. We utilized this model to screen a library of targeted single-gene deletion mutants to identify novel genes of Salmonella Typhimurium required for survival during enteric infection. Fifty-four candidate mutants were strongly selected, including numerous mutations in genes known to be important for gastrointestinal survival of salmonellae. Three genes with previously unproven phenotypes in gastrointestinal infection were tested in bovine ligated ileal loops. Two of these mutants, STM3602 and STM3846, recapitulated the phenotype observed in the mutant pool. Complementation experiments successfully reversed the observed phenotypes, directly linking these genes to the colonization defects of the corresponding mutant strains. STM3602 encodes a putative transcriptional regulator that may be involved in phosphonate utilization, and STM3846 encodes a retron reverse transcriptase that produces a unique RNA-DNA hybrid molecule called multicopy single-stranded DNA. The genes identified in this study represent an exciting new class of virulence determinants for further mechanistic study to elucidate the strategies employed by Salmonella to survive within the small intestines of cattle.

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Section: Figmentioning

confidence: 99%

Novel Determinants of Intestinal Colonization of Salmonella enterica Serotype Typhimurium Identified in Bovine Enteric Infection

et al. 2013

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“…These endogenous peptides are induced during exposure to enteric pathogens in an attempt to protect the host from infection (1). It is increasingly apparent that antimicrobial peptides also play an essential role in the maintenance of intestinal homeostasis by limiting microbial-epithelium interactions and preventing unnecessary microbe-driven inflammation (2).…”

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confidence: 99%

Differential Induction of Antimicrobial REGIII by the Intestinal Microbiota and Bifidobacterium breve NCC2950

Natividad

Hayes

Motta

et al. 2013

Appl Environ Microbiol

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The intestinal microbiota is a key determinant of gut homeostasis, which is achieved, in part, through regulation of antimicrobial peptide secretion. The aim of this study was to determine the efficiency by which members of the intestinal microbiota induce the antimicrobial peptide REGIII and to elucidate the underlying pathways. We showed that germfree mice have low levels of REGIII-␥ in their ileum and colon compared to mice with different intestinal microbiota backgrounds. Colonization with a microbiota of low diversity (altered Schaedler flora) did not induce the expression of REGIII-␥ as effectively as a complex community (specific pathogen free). Monocolonization with the probiotic Bifidobacterium breve, but not with the nonprobiotic commensal Escherichia coli JM83, upregulated REGIII-␥ expression. Induction of REGIII-␥ by B. breve was abrogated in mice lacking MyD88 and Ticam1 signaling. Both live and heat-inactivated B. breve but not spent culture medium from B. breve induced the expression of REGIII-␣, the human ortholog and homolog of REGIII-␥, in human colonic epithelial cells (Caco-2). Taken together, the results suggest that REGIII-␥ expression in the intestine correlates with the richness of microbiota composition. Also, specific bacteria such as Bifidobacterium breve NCC2950 effectively induce REGIII production in the intestine via the MyD88-Ticam1 pathway. Treatment with this probiotic may enhance the mucosal barrier and protect the host from infection and inflammation.

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“…Once germinated, the vegetative cells in the colon encounter an unreceptive environment (1). Competition with the normal flora, immune responses, gastric fluids (2), and specialized antimicrobial peptides all act against a developing infection. Moreover, the physical barrier formed by a layer of glycoproteins (mucins) covering the underlying epithelial cells forms a major hurdle for firm adhesion.…”

mentioning

confidence: 99%

A Novel Secreted Metalloprotease (CD2830) from Clostridium difficile Cleaves Specific Proline Sequences in LPXTG Cell Surface Proteins

Hensbergen

Klychnikov

Bakker

et al. 2014

Molecular & Cellular Proteomics

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Bacterial secreted proteins constitute a biologically important subset of proteins involved in key processes related to infection such as adhesion, colonization, and dissemination. Bacterial extracellular proteases, in particular, have attracted considerable attention, as they have been shown to be indispensable for bacterial virulence.Here, we analyzed the extracellular subproteome of Clostridium difficile and identified a hypothetical protein, CD2830, as a novel secreted metalloprotease. Following the identification of a CD2830 cleavage site in human HSP90␤, a series of synthetic peptide substrates was used to identify the favorable CD2830 cleavage motif. This motif was characterized by a high prevalence of proline residues. Intriguingly, CD2830 has a preference for cleaving Pro-Pro bonds, unique among all hitherto described proteases. Strikingly, within the C. difficile proteome two putative adhesion molecules, CD2831 and CD3246, were identified that contain multiple CD2830 cleavage sites (13 in total). We subsequently found that CD2830 efficiently cleaves CD2831 between two prolines at all predicted cleavage sites. Moreover, native CD2830, secreted by live cells, cleaves endogenous CD2831 and CD3246.These findings highlight CD2830 as a highly specific endoproteinase with a preference for proline residues Clostridium difficile is an anaerobic, Gram-positive, sporeforming bacterium. Human intake of spores occurs through the fecal-oral route. Upon leaving the stomach and becoming exposed to bile acids in the small intestine, the C. difficile spores germinate. Once germinated, the vegetative cells in the colon encounter an unreceptive environment (1). Competition with the normal flora, immune responses, gastric fluids (2), and specialized antimicrobial peptides all act against a developing infection. Moreover, the physical barrier formed by a layer of glycoproteins (mucins) covering the underlying epithelial cells forms a major hurdle for firm adhesion.Many enteric pathogens express factors that reduce competition, allow evasion of host immune responses, and promote adhesion and/or invasion of tissues. These virulence factors are located in the cell membrane or wall (controlling adhesion and protection) or are secreted (modifying the surrounding environment). The best studied virulence factors in C. difficile are the toxins TcdA and TcdB (3, 4), which cause destruction of the intestinal barrier by disrupting the epithelial actin cytoskeleton. It is speculated that the subsequent increased permeability of the intestinal epithelium leads to increased exudation of fluids, including nutritional substances. Damage to the intestinal mucosa causes the main symptoms of C. difficile infection, including pseudomembranous colitis (1).Data illustrating how C. difficile circumvents host defense mechanisms are limited. As an example, in response to attack by antimicrobial peptides, C. difficile expresses a set of genes that change the surface charge, thereby diminishing the interaction of cationic antimicrobial peptides on th...

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Intestinal antimicrobial peptides during homeostasis, infection, and disease

Cited by 186 publications

References 195 publications

Novel Determinants of Intestinal Colonization of Salmonella enterica Serotype Typhimurium Identified in Bovine Enteric Infection

Novel Determinants of Intestinal Colonization of Salmonella enterica Serotype Typhimurium Identified in Bovine Enteric Infection

Differential Induction of Antimicrobial REGIII by the Intestinal Microbiota and Bifidobacterium breve NCC2950

A Novel Secreted Metalloprotease (CD2830) from Clostridium difficile Cleaves Specific Proline Sequences in LPXTG Cell Surface Proteins

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