Abstract

Nearly all of the known virulence factors synthesized by Bordetella pertussis, the causative agent of human whooping cough, and Bordetella bronchiseptica, which causes respiratory disease in other animals, are positively regulated by the Bvg signal transduction system. Bvg also negatively regulates production of a class of outer membrane proteins in B. pertussis and flagella synthesis and motility in B. bronchiseptica. The ability of Bordetella species to alternate between distinct phenotypic phases in response to environmental conditions has been recognized for many years, yet the role of Bvg- mediated signal transduction in the infectious cycle is unknown. The investigators' experiments will focus on the following questions: 1) How and why are Bordetella virulence genes regulated by Bvg, and 2) What are the functions of the regulated gene products? To address these they will use a comparative approach by conducting parallel studies with the human pathogen B. pertussis and the closely related animal pathogen B. bronchiseptica. They have established in vitro assays for studying the biochemistry of signal transduction, genetic methods for manipulating the virulence regulon, and natural host- animal models for characterizing respiratory tract infection. These form the foundation for this proposal. The research plan begins with an examination of molecular aspects of signal transduction using purified proteins and measurements of BvgA and BvgS function in E. coli. They will also address mechanisms of signal recognition by BvgS and these basic studies will facilitate an in vivo analysis. The effect of alterations in Bvg signal transduction pathways will then be assessed using animal models for B. bronchiseptica and B. pertussis. Studies with defined mutants will be accompanied by the development of a method for directly determining the phase of Bordetella populations in respiratory tissue. The relationship between the virulence regulons of B. pertussis and B. bronchiseptica will be investigated next, with specific emphasis on loci that are negatively regulated by Bvg. Finally, they will assess the functions of putative adhesins and toxins during infection of natural hosts by B. bronchiseptica. A novel approach using """"""""ectopic expression"""""""" will be used for this purpose. By considering the Bvg regulon from a broad perspective they hope to discover its role in pathogenesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI038417-05
Application #
2887059
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Klein, David L
Project Start
1995-07-01
Project End
2001-04-14
Budget Start
1999-07-01
Budget End
2001-04-14
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Guo, Huatao; Arambula, Diego; Ghosh, Partho et al. (2014) Diversity-generating Retroelements in Phage and Bacterial Genomes. Microbiol Spectr 2:
Medhekar, Bob; Shrivastava, Ruchi; Mattoo, Seema et al. (2009) Bordetella Bsp22 forms a filamentous type III secretion system tip complex and is immunoprotective in vitro and in vivo. Mol Microbiol 71:492-504
French, Christopher T; Panina, Ekaterina M; Yeh, Sylvia H et al. (2009) The Bordetella type III secretion system effector BteA contains a conserved N-terminal motif that guides bacterial virulence factors to lipid rafts. Cell Microbiol 11:1735-49
Cummings, C A; Bootsma, H J; Relman, D A et al. (2006) Species- and strain-specific control of a complex, flexible regulon by Bordetella BvgAS. J Bacteriol 188:1775-85
Panina, Ekaterina M; Mattoo, Seema; Griffith, Natasha et al. (2005) A genome-wide screen identifies a Bordetella type III secretion effector and candidate effectors in other species. Mol Microbiol 58:267-79
Widney, Daniel P; Hu, Yan; Foreman-Wykert, Amy K et al. (2005) CXCR3 and its ligands participate in the host response to Bordetella bronchiseptica infection of the mouse respiratory tract but are not required for clearance of bacteria from the lung. Infect Immun 73:485-93
Kozak, Natalia A; Mattoo, Seema; Foreman-Wykert, Amy K et al. (2005) Interactions between partner switcher orthologs BtrW and BtrV regulate type III secretion in Bordetella. J Bacteriol 187:5665-76
Liu, Minghsun; Gingery, Mari; Doulatov, Sergei R et al. (2004) Genomic and genetic analysis of Bordetella bacteriophages encoding reverse transcriptase-mediated tropism-switching cassettes. J Bacteriol 186:1503-17
Mattoo, Seema; Yuk, Ming H; Huang, Lisa L et al. (2004) Regulation of type III secretion in Bordetella. Mol Microbiol 52:1201-14
Stockbauer, Kathryn E; Foreman-Wykert, Amy K; Miller, Jeff F (2003) Bordetella type III secretion induces caspase 1-independent necrosis. Cell Microbiol 5:123-32

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