title: Identification of a conserved bacterial protein secretion system in Vibrio cholerae using the Dictyostelium host model system.
abstract: The bacterium Vibrio cholerae, like other human pathogens that reside in environmental reservoirs, survives predation by unicellular eukaryotes. Strains of the O1 and O139 serogroups cause cholera, whereas non-O1/non-O139 strains cause human infections through poorly defined mechanisms. Using Dictyostelium discoideum as a model host, we have identified a virulence mechanism in a non-O1/non-O139 V. cholerae strain that involves extracellular translocation of proteins that lack N-terminal hydrophobic leader sequences. Accordingly, we have named these genes "VAS" genes for virulence-associated secretion, and we propose that these genes encode a prototypic "type VI" secretion system. We show that vas genes are required for cytotoxicity of V. cholerae cells toward Dictyostelium amoebae and mammalian J774 macrophages by a contact-dependent mechanism. A large number of Gram-negative bacterial pathogens carry genes homologous to vas genes and potential effector proteins secreted by this pathway (i.e., hemolysin-coregulated protein and VgrG). Mutations in vas homologs in other bacterial species have been reported to attenuate virulence in animals and cultured macrophages. Thus, the genes encoding the VAS-related, type VI secretion system likely play an important conserved function in microbial pathogenesis and represent an additional class of targets for vaccine and antimicrobial drug-based therapies.
authors.affiliation: Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pukatzki
authors.forename: Amy T
authors.initials: AT
authors.lastname: Ma
authors.forename: Derek
authors.initials: D
authors.lastname: Sturtevant
authors.forename: Bryan
authors.initials: B
authors.lastname: Krastins
authors.forename: David
authors.initials: D
authors.lastname: Sarracino
authors.forename: William C
authors.initials: WC
authors.lastname: Nelson
authors.forename: John F
authors.initials: JF
authors.lastname: Heidelberg
authors.forename: John J
authors.initials: JJ
authors.lastname: Mekalanos
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry; D002460:Cell Line; D022121:Cholera Vaccines; D004251:DNA Transposable Elements; D004023:Dictyostelium / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D015964:Gene Expression Regulation, Bacterial; D015723:Gene Library; D005798:Genes, Bacterial; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D021381:Protein Transport; D013997:Time Factors; D014734:Vibrio cholerae / Q000378:metabolism*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D022121:Cholera Vaccines; D004251:DNA Transposable Elements