Dataset Information

Vibrio cholerae RND efflux systems: mediators of stress responses, colonization and pathogenesis.

ABSTRACT: Resistance Nodulation Division (RND) efflux systems are ubiquitous transporters in gram-negative bacteria that provide protection against antimicrobial agents and thereby enhance survival in virtually all environments these prokaryotes inhabit. Vibrio cholerae is a dual lifestyle enteric pathogen that spends much of its existence in aquatic environments. An unwitting encounter with a human host can lead to V. cholerae intestinal colonization by strains that encode cholera toxin and toxin co-regulated pilus virulence factors leading to potentially fatal cholera diarrhea and dissemination in the environment. Adaptive response mechanisms to host factors encountered by these pathogens are therefore critical both to engage survival mechanisms such as RND-mediated transporters and to induce timely expression of virulence factors. Sensing of cues encountered in the host may therefore activate more than protective responses such as efflux systems, but also be coordinated to initiate expression of virulence factors. This review summarizes recent advances that contribute towards the understanding of RND efflux physiological functions and how the transport systems interface with the regulation of virulence factor production in V. cholerae.

SUBMITTER: Bina XR

PROVIDER: S-EPMC10225521 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Vibrio cholerae RND efflux systems: mediators of stress responses, colonization and pathogenesis.

Bina X Renee XR Bina James E JE

Frontiers in cellular and infection microbiology 20230515

Resistance Nodulation Division (RND) efflux systems are ubiquitous transporters in gram-negative bacteria that provide protection against antimicrobial agents and thereby enhance survival in virtually all environments these prokaryotes inhabit. <i>Vibrio cholerae</i> is a dual lifestyle enteric pathogen that spends much of its existence in aquatic environments. An unwitting encounter with a human host can lead to <i>V. cholerae</i> intestinal colonization by strains that encode cholera toxin and ...[more]

PMID: 37256112

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Project description:Artemisinin (ARS) displayed bactericidal activity against Vibrio cholerae. To assess the mechanistic details of its antibacterial action, we have isolated V. cholerae mutants with enhanced ARS resistance and identified a gene (VCA0767) whose loss-of-function resulted in the ARS resistance phenotypes. This gene (atrR) encodes a TetR family transcriptional regulator, and its deletion mutant displayed the reduction in ARS-induced ROS formation and DNA damage. Transcriptomic analysis revealed that the genes encoding a resistance-nodulation-cell division (RND) efflux pump operon (vexRAB) and the outer membrane component (tolC) were highly upregulated in the artR mutant, suggesting that AtrR might act as a negative regulator of this operon and tolC. Gene deletion of vexR, vexB, or tolC abrogated the ARS resistance of the atrR mutant, and more importantly, the ectopic expression of VexAB-TolC was sufficient for the ARS resistance, indicating that the increased expression of the VexAB-TolC efflux system is necessary and sufficient for the ARS resistance of the atrR mutant. The cytoplasmic accumulation of ARS was compromised in the vexBtolC mutant, suggesting that the VexAB-TolC might be the primary efflux system exporting ARS to reduce its toxicity inside of the bacterial cells. The atrR mutant displayed resistance to erythromycin as well in a VexR-dependent manner. This result suggests that AtrR may act as a global regulator responsible for preventing intracellular accumulation of toxic chemicals by enhancing the RND efflux system.IMPORTANCEDrug efflux protein complexes or efflux pumps are considered as the major determinants of multiple antimicrobial resistance by exporting a wide range of structurally diverse antibiotics in bacterial pathogens. Despite the clinical significance of the increased expression of the efflux pumps, their substrate specificity and regulation mechanisms are poorly understood. Here, we demonstrated that VexAB-TolC, a resistance-nodulation-cell division (RND) efflux pump of V. cholerae, is responsible for the resistance to artemisinin (ARS), an antimalarial drug with bactericidal activity. Furthermore, we newly identified AtrR, a TetR family repressor, as a global regulator for VexRAB and the common outer membrane channel, TolC, where VexR functions as the pathway-specific regulator of the vexAB operon. Our findings will help improve our insight into a broad range of substrate specificity of the VexAB-TolC system and highlight the complex regulatory networks of the multiple RND efflux systems during V. cholerae pathogenesis.

Project description:Vibrio cholerae is an important human pathogen and environmental microflora species that can both propagate in the human intestine and proliferate in zooplankton and aquatic organisms. Cholera is transmitted through food and water. In recent years, outbreaks caused by V. cholerae-contaminated soft-shelled turtles, contaminated mainly with toxigenic serogroup O139, have been frequently reported, posing a new foodborne disease public health problem. In this study, the colonization by toxigenic V. cholerae on the body surfaces and intestines of soft-shelled turtles was explored. Preferred colonization sites on the turtle body surfaces, mainly the carapace and calipash of the dorsal side, were observed for the O139 and O1 strains. Intestinal colonization was also found. The colonization factors of V. cholerae played different roles in the colonization of the soft-shelled turtle's body surface and intestine. Mannose-sensitive hemagglutinin (MSHA) of V. cholerae was necessary for body surface colonization, but no roles were found for toxin-coregulated pili (TCP) or N-acetylglucosamine-binding protein A (GBPA). Both TCP and GBPA play important roles for colonization in the intestine, whereas the deletion of MSHA revealed only a minor colonization-promoting role for this factor. Our study demonstrated that V. cholerae can colonize the surfaces and the intestines of soft-shelled turtles and indicated that the soft-shelled turtles played a role in the transmission of cholera. In addition, this study showed that the soft-shelled turtle has potential value as an animal model in studies of the colonization and environmental adaption mechanisms of V. cholerae in aquatic organisms.IMPORTANCE Cholera is transmitted through water and food. Soft-shelled turtles contaminated with Vibrio cholerae (commonly the serogroup O139 strains) have caused many foodborne infections and outbreaks in recent years, and they have become a foodborne disease problem. Except for epidemiological investigations, no experimental studies have demonstrated the colonization by V. cholerae on soft-shelled turtles. The present studies will benefit our understanding of the interaction between V. cholerae and the soft-shelled turtle. We demonstrated the colonization by V. cholerae on the soft-shelled turtle's body surface and in the intestine and revealed the different roles of major V. cholerae factors for colonization on the body surface and in the intestine. Our work provides experimental evidence for the role of soft-shelled turtles in cholera transmission. In addition, this study also shows the possibility for the soft-shelled turtle to serve as a new animal model for studying the interaction between V. cholerae and aquatic hosts.

Dataset Information

Vibrio cholerae RND efflux systems: mediators of stress responses, colonization and pathogenesis.

Publications

Vibrio cholerae RND efflux systems: mediators of stress responses, colonization and pathogenesis.

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