Review

* Author for correspondence

Research Center of Transport Protein for Medical Innovation & Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Rd, Rajathevi, Bangkok 10400, Thailand.

Email the corresponding author at chatchai.mua@mahidol.ac.th

Varanuj Chatsudthipong

Research Center of Transport Protein for Medical Innovation & Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Rd, Rajathevi, Bangkok 10400, Thailand

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Published Online:8 May 2013https://doi.org/10.4155/fmc.13.42

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Abstract

Cholera is a diarrheal disease that remains an important global health problem with several hundreds of thousands of reported cases each year. This disease is caused by intestinal infection with Vibrio cholerae, which is a highly motile gram-negative bacterium with a single-sheathed flagellum. In the course of cholera pathogenesis, V. cholerae expresses a transcriptional activator ToxT, which subsequently transactivates expressions of two crucial virulence factors: toxin-coregulated pilus and cholera toxin (CT). These factors are responsible for intestinal colonization of V. cholerae and induction of fluid secretion, respectively. In intestinal epithelial cells, CT binds to GM1 ganglioside receptors on the apical membrane and undergoes retrograde vesicular trafficking to endoplasmic reticulum, where it exploits endoplasmic reticulum-associated protein degradation systems to release a catalytic A1 subunit of CT (CT A1) into cytoplasm. CT A1, in turn, catalyzes ADP ribosylation of α subunits of stimulatory G proteins, leading to a persistent activation of adenylate cyclase and an elevation of intracellular cAMP. Increased intracellular cAMP in human intestinal epithelial cells accounts for pathogenesis of profuse diarrhea and severe fluid loss in cholera. This review provides an overview of the pathophysiology of cholera diarrhea and discusses emerging drug targets for cholera, which include V. cholerae virulence factors, V. cholerae motility, CT binding to GM1 receptor, CT internalization and intoxication, as well as cAMP metabolism and transport proteins involved in cAMP-activated Cl^- secretion. Future directions and perspectives of research on drug discovery and development for cholera are discussed.

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Acknowledgement

The authors would like to thank C Pholpramool for critical reading of this review.

Financial & competing interests disclosure

Supported by grants from Mahidol University, the Office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative, and grant MRG5380125 from Thailand Research Fund, the Office of the Higher Education Commission and Mahidol University to C Muanprasat. A grant BRG5380005 from Thailand Research Fund to V Chatsudthipong is also gratefully acknowledged. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Cholera: pathophysiology and emerging therapeutic targets

Abstract

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