title: Cholera: pathophysiology and emerging therapeutic targets.
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.
authors: Research Center of Transport Protein for Medical Innovation & Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Rd, Rajathevi, Bangkok 10400, Thailand. chatchai.mua@mahidol.ac.th
authors: Chatchai
authors: C
authors: Muanprasat
authors: Varanuj
authors: V
authors: Chatsudthipong
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects; D002771:Cholera / Q000188:drug therapy / Q000382:microbiology / Q000503:physiopathology*; D002772:Cholera Toxin / Q000737:chemistry / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D011956:Receptors, Cell Surface / Q000378:metabolism; D014734:Vibrio cholerae / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity; D014774:Virulence / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D011956:Receptors, Cell Surface; C034993:ganglioside receptor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002772:Cholera Toxin; D000242:Cyclic AMP