title: Differential regulation of type III secretion and virulence genes in Bordetella pertussis and Bordetella bronchiseptica by a secreted anti-σ factor.
abstract: The BvgAS phosphorelay regulates ∼10% of the annotated genomes of Bordetella pertussis and Bordetella bronchiseptica and controls their infectious cycles. The hierarchical organization of the regulatory network allows the integration of contextual signals to control all or specific subsets of BvgAS-regulated genes. Here, we characterize a regulatory node involving a type III secretion system (T3SS)-exported protein, BtrA, and demonstrate its role in determining fundamental differences in T3SS phenotypes among Bordetella species. We show that BtrA binds and antagonizes BtrS, a BvgAS-regulated extracytoplasmic function (ECF) sigma factor, to couple the secretory activity of the T3SS apparatus to gene expression. In B. bronchiseptica, a remarkable spectrum of expression states can be resolved by manipulating btrA, encompassing over 80 BtrA-activated loci that include genes encoding toxins, adhesins, and other cell surface proteins, and over 200 BtrA-repressed genes that encode T3SS apparatus components, secretion substrates, the BteA effector, and numerous additional factors. In B. pertussis, BtrA retains activity as a BtrS antagonist and exerts tight negative control over T3SS genes. Most importantly, deletion of btrA in B. pertussis revealed T3SS-mediated, BteA-dependent cytotoxicity, which had previously eluded detection. This effect was observed in laboratory strains and in clinical isolates from a recent California pertussis epidemic. We propose that the BtrA-BtrS regulatory node determines subspecies-specific differences in T3SS expression among Bordetella species and that B. pertussis is capable of expressing a full range of T3SS-dependent phenotypes in the presence of appropriate contextual cues.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095;
authors.forename: Umesh
authors.initials: U
authors.lastname: Ahuja
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095;
authors.forename: Bhumika
authors.initials: B
authors.lastname: Shokeen
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095;
authors.forename: Ning
authors.initials: N
authors.lastname: Cheng
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095;
authors.forename: Yeonjoo
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Department of Neurology, University of California, Los Angeles, CA 90095;
authors.forename: Charles
authors.initials: C
authors.lastname: Blum
authors.affiliation: Department of Neurology, University of California, Los Angeles, CA 90095;
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095; California NanoSystems Institute, University of California, Los Angeles, CA 90095 jfmiller@ucla.edu.
authors.forename: Jeff F
authors.initials: JF
authors.lastname: Miller
mesh_terms: D016950:Bordetella bronchiseptica / Q000235:genetics / Q000821:virology*; D001886:Bordetella pertussis / Q000235:genetics / Q000821:virology*; D005798:Genes, Bacterial; D012808:Sigma Factor / Q000037:antagonists & inhibitors*; D014774:Virulence / Q000235:genetics*
chemical_list: D012808:Sigma Factor
keywords: Bordetella; ECF sigma factor; T3SS; host adaptation; virulence gene regulation