title: Bile salt-induced intermolecular disulfide bond formation activates Vibrio cholerae virulence.
abstract: To be successful pathogens, bacteria must often restrict the expression of virulence genes to host environments. This requires a physical or chemical marker of the host environment as well as a cognate bacterial system for sensing the presence of a host to appropriately time the activation of virulence. However, there have been remarkably few such signal-sensor pairs identified, and the molecular mechanisms for host-sensing are virtually unknown. By directly applying a reporter strain of Vibrio cholerae, the causative agent of cholera, to a thin layer chromatography (TLC) plate containing mouse intestinal extracts, we found two host signals that activate virulence gene transcription. One of these was revealed to be the bile salt taurocholate. We then show that a set of bile salts cause dimerization of the transmembrane transcription factor TcpP by inducing intermolecular disulfide bonds between cysteine (C)-207 residues in its periplasmic domain. Various genetic and biochemical analyses led us to propose a model in which the other cysteine in the periplasmic domain, C218, forms an inhibitory intramolecular disulfide bond with C207 that must be isomerized to form the active C207-C207 intermolecular bond. We then found bile salt-dependent effects of these cysteine mutations on survival in vivo, correlating to our in vitro model. Our results are a demonstration of a mechanism for direct activation of the V. cholerae virulence cascade by a host signal molecule. They further provide a paradigm for recognition of the host environment in pathogenic bacteria through periplasmic cysteine oxidation.
authors: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Menghua
authors: M
authors: Yang
authors: Zhi
authors: Z
authors: Liu
authors: Chambers
authors: C
authors: Hughes
authors: Andrew M
authors: AM
authors: Stern
authors: Hui
authors: H
authors: Wang
authors: Zengtao
authors: Z
authors: Zhong
authors: Biao
authors: B
authors: Kan
authors: William
authors: W
authors: Fenical
authors: Jun
authors: J
authors: Zhu
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology*; D002771:Cholera / Q000209:etiology / Q000378:metabolism / Q000382:microbiology; D004195:Disease Models, Animal; D004220:Disulfides / Q000737:chemistry; D005798:Genes, Bacterial; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D055503:Protein Multimerization / Q000187:drug effects; D015398:Signal Transduction; D013656:Taurocholic Acid / Q000378:metabolism / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014734:Vibrio cholerae / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D014774:Virulence / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; D001647:Bile Acids and Salts; D004220:Disulfides; C097244:TCPP protein, Vibrio cholerae; D014157:Transcription Factors; D013656:Taurocholic Acid