To be successful pathogens, bacteria must possess mechanisms for sensing specific host environments, processing changes, and making appropriate adaptations. In many bacteria, expression of disparate virulence factors is controlled by a common regulatory system. Virulence gene expression in Bacillus anthracis, the causative agent of anthrax, is a unique example of a coordinately regulated response to a specific host-related signal. Virulent Bacillus anthracis produce two known virulence factors, a tripartite toxin, composed of edema factor, lethal factor, and protective antigen, and a poly-D-glutamic acid capsule. The toxin and capsule genes are located on plasmids pXO1 (185 kb) and pXO2 (95 kb), respectively. Synthesis of these virulence factors is enhanced when B. anthracis is grown in elevated levels of carbon dioxide. CO2 is postulated to be a physiologically significant signal during anthrax infection. Concentrations of bicarbonate and CO2 in mammalian tissues are comparable to those that activate toxin and capsule synthesis during in vitro growth. The long term goal of these studies is to elucidate the molecular basis for virulence gene expression in B. anthracis. The PI has determined that the trans-acting regulatory gene atxA is required for CO2-induced transcription of all three toxin genes during growth in vitro. AtxA also activates toxin expression in vivo; atxA mutants are avirulent in mice and mice infected with atxA- strains show a decreased immunological response to the toxin proteins. Another gene, acpA, has been implicated in CO2-induced capsule gene expression. In this study, the PI will further probe regulation of toxin and capsule synthesis and investigate whether B. anthracis harbors additional virulence genes.
The specific aims are to: 1) identify atxA-regulated non-toxin genes and test the effect of these genes on virulence; 2) identify and characterize additional regulatory genes that affect toxin expression, 3) investigate the physiological significance of acpA expression in cells harboring atxA. These studies will provide information relevant to the pathogenesis of anthrax disease and increase knowledge concerning host-parasite relationships and signal transduction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033537-07
Application #
2886811
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Baker, Phillip J
Project Start
1992-12-01
Project End
2003-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Dale, Jennifer L; Raynor, Malik J; Ty, Maureen C et al. (2018) A Dual Role for the Bacillus anthracis Master Virulence Regulator AtxA: Control of Sporulation and Anthrax Toxin Production. Front Microbiol 9:482
Raynor, Malik J; Roh, Jung-Hyeob; Widen, Stephen G et al. (2018) Regulons and protein-protein interactions of PRD-containing Bacillus anthracis virulence regulators reveal overlapping but distinct functions. Mol Microbiol :
Swick, Michelle C; Koehler, Theresa M; Driks, Adam (2016) Surviving Between Hosts: Sporulation and Transmission. Microbiol Spectr 4:
Scarff, Jennifer M; Raynor, Malik J; Seldina, Yuliya I et al. (2016) The roles of AtxA orthologs in virulence of anthrax-like Bacillus cereus G9241. Mol Microbiol 102:545-561
Terwilliger, Austen; Swick, Michelle C; Pflughoeft, Kathryn J et al. (2015) Bacillus anthracis Overcomes an Amino Acid Auxotrophy by Cleaving Host Serum Proteins. J Bacteriol 197:2400-11
Hammerstrom, Troy G; Horton, Lori B; Swick, Michelle C et al. (2015) Crystal structure of Bacillus anthracis virulence regulator AtxA and effects of phosphorylated histidines on multimerization and activity. Mol Microbiol 95:426-41
Pflughoeft, Kathryn J; Swick, Michelle C; Engler, David A et al. (2014) Modulation of the Bacillus anthracis secretome by the immune inhibitor A1 protease. J Bacteriol 196:424-35
Lovchik, Julie A; Drysdale, Melissa; Koehler, Theresa M et al. (2012) Expression of either lethal toxin or edema toxin by Bacillus anthracis is sufficient for virulence in a rabbit model of inhalational anthrax. Infect Immun 80:2414-25
Dale, Jennifer L; Raynor, Malik J; Dwivedi, Prabhat et al. (2012) cis-Acting elements that control expression of the master virulence regulatory gene atxA in Bacillus anthracis. J Bacteriol 194:4069-79
Pflughoeft, Kathryn J; Sumby, Paul; Koehler, Theresa M (2011) Bacillus anthracis sin locus and regulation of secreted proteases. J Bacteriol 193:631-9

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