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A Periplasmic Antimicrobial Peptide-Binding Protein Is Required for Stress Survival in Vibrio cholerae.

ABSTRACT: Vibrio cholerae must sense and respond appropriately to stresses encountered in the aquatic environment and the human host. One stress encountered in both environments is exposure to antimicrobial peptides (AMPs), produced as a part of the innate immune response by all multicellular organisms. Previous transcriptomic analysis demonstrated that expression of Stress-inducible protein A (SipA) (VCA0732), a hypothetical protein, was highly induced by AMP exposure and was dependent on a specific uncharacterized two-component system. In order to better understand role of this protein in stress relief, we examined whether it shared any of the phenotypes reported for its homologs. SipA is required for survival in the presence of two other stressors, cadmium chloride and hydrogen peroxide, and it localizes to the bacterial periplasm, similar to its homologs. We also found that SipA physically interacts with OmpA. Importantly, we found that SipA binds AMPs in the bacterial periplasm. This suggests a model where SipA may act as a molecular chaperone, binding AMPs that enter the periplasm and delivering them to OmpA for removal from the cell. While El Tor V. cholerae strains lacking SipA do not show a survival defect in the presence of AMPs, we found that Classical sipA mutants are less able to survive in the presence of AMPs. This phenotype is likely masked in the El Tor background due to a functional lipid A modification system that increases AMP resistance in these strains. In summary, we have identified a protein that contributes to a novel mechanism of stress relief in V. cholerae.

SUBMITTER: Saul-McBeth J

PROVIDER: S-EPMC6370654 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A Periplasmic Antimicrobial Peptide-Binding Protein Is Required for Stress Survival in <i>Vibrio cholerae</i>.

Saul-McBeth Jessica J Matson Jyl S JS

Frontiers in microbiology 20190205

<i>Vibrio cholerae</i> must sense and respond appropriately to stresses encountered in the aquatic environment and the human host. One stress encountered in both environments is exposure to antimicrobial peptides (AMPs), produced as a part of the innate immune response by all multicellular organisms. Previous transcriptomic analysis demonstrated that expression of Stress-inducible protein A (SipA) (VCA0732), a hypothetical protein, was highly induced by AMP exposure and was dependent on a specif ...[more]

PMID: 30804918

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Project description:LysR-type transcriptional regulators (LTTRs) are the largest, most diverse family of prokaryotic transcription factors, with regulatory roles spanning metabolism, cell growth and division, and pathogenesis. Using a sequence-defined transposon mutant library, we screened a panel of V. cholerae El Tor mutants to identify LTTRs required for host intestinal colonization. Surprisingly, out of 38 LTTRs, only one severely affected intestinal colonization in the suckling mouse model of cholera: the methionine metabolism regulator, MetR. Genetic analysis of genes influenced by MetR revealed that glyA1 and metJ were also required for intestinal colonization. Chromatin immunoprecipitation of MetR and quantitative reverse transcription-PCR (qRT-PCR) confirmed interaction with and regulation of glyA1, indicating that misregulation of glyA1 is likely responsible for the colonization defect observed in the metR mutant. The glyA1 mutant was auxotrophic for glycine but exhibited wild-type trimethoprim sensitivity, making folate deficiency an unlikely cause of its colonization defect. MetJ regulatory mutants are not auxotrophic but are likely altered in the regulation of amino acid-biosynthetic pathways, including those for methionine, glycine, and serine, and this misregulation likely explains its colonization defect. However, mutants defective in methionine, serine, and cysteine biosynthesis exhibited wild-type virulence, suggesting that these amino acids can be scavenged in vivo. Taken together, our results suggest that glycine biosynthesis may be required to alleviate an in vivo nutritional restriction in the mouse intestine; however, additional roles for glycine may exist. Irrespective of the precise nature of this requirement, this study illustrates the importance of pathogen metabolism, and the regulation thereof, as a virulence factor. Vibrio cholerae continues to be a severe cause of morbidity and mortality in developing countries. Identification of V. cholerae factors critical to disease progression offers the potential to develop or improve upon therapeutics and prevention strategies. To increase the efficiency of virulence factor discovery, we employed a regulator-centric approach to multiplex our in vivo screening capabilities and allow whole regulons in V. cholerae to be interrogated for pathogenic potential. We identified MetR as a new virulence regulator and serine hydroxymethyltransferase GlyA1 as a new MetR-regulated virulence factor, both required by V. cholerae to colonize the infant mouse intestine. Bacterial metabolism is a prerequisite to virulence, and current knowledge of in vivo metabolism of pathogens is limited. Here, we expand the known role of amino acid metabolism and regulation in virulence and offer new insights into the in vivo metabolic requirements of V. cholerae within the mouse intestine.

Dataset Information

A Periplasmic Antimicrobial Peptide-Binding Protein Is Required for Stress Survival in Vibrio cholerae.

Publications

A Periplasmic Antimicrobial Peptide-Binding Protein Is Required for Stress Survival in <i>Vibrio cholerae</i>.

Similar Datasets

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