The Bordetella genus includes several closely related subspecies of Gram-negative bacteria that colonize ciliated respiratory epithelial surfaces in mammals. In addition to their importance as infectious agents, members of the Bordetella genus provide excellent models for probing bacterial-host interactions. The availability of highly related subspecies with different host adaptations allows comparative studies of pathogenesis. Although B. pertussis is exclusively adapted to humans, B. bronchiseptica has a remarkably broad host range that includes a variety of laboratory animals. B. bronchiseptica models allow assessments of the molecular basis of pathogenesis in the context of natural host-parasite interactions. We have identified a type III secretion system (TTSS) in B. bronchiseptica that appears to play a key role in facilitating persistent infection of the respiratory epithelium. Recent results indicate that type III secretion (TTS) apparatus genes, regulatory genes, and genes encoding secreted proteins are actively transcribed in B. pertussis. Furthermore, the BtrS regulatory system that controls TTS is present and functional. The objective of this proposal is to conduct a comprehensive comparative analysis of TTS in Bordetella subspecies infectious for humans and other animals. Results from our studies will contribute to a fundamental understanding of mechanisms of pathogenesis and the evolution of bacterial virulence. Specifically, we propose to: 1. Conduct a comparative analysis of the BtrS regulons in Bordetella subspecies. BtrS is a newly identified sigma factor that sits at the top of a complex regulatory hierarchy controlling expression of type III secretion loci and other genes. These studies have the potential to discover novel virulence factors and regulatory mechanisms. 2. Determine the roles of """"""""partner switcher"""""""" homologs in the regulation of type III secretion. Partner switching represents a new and expanding paradigm in bacterial regulation. We will test the hypothesis that differences in the behavior of the BtrU,V,W partner switching complex accounts for differences in the control of type III secretion between Bordetella subspecies. 3. Investigate the effects of type III secretion and other BtrS-regulated phenotypes during respiratory tract infection by B. pertussis and B. bronchiseptica.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI061598-03
Application #
7079312
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Khambaty, Farukh M
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$370,940
Indirect Cost
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Ahuja, Umesh; Liu, Minghsun; Tomida, Shuta et al. (2012) Phenotypic and genomic analysis of hypervirulent human-associated Bordetella bronchiseptica. BMC Microbiol 12:167
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
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Guo, Huatao; Tse, Longping V; Barbalat, Roman et al. (2008) Diversity-generating retroelement homing regenerates target sequences for repeated rounds of codon rewriting and protein diversification. Mol Cell 31:813-23
Miller, Jason L; Le Coq, Johanne; Hodes, Asher et al. (2008) Selective ligand recognition by a diversity-generating retroelement variable protein. PLoS Biol 6:e131
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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

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