Dr. Theresa M. Koehler
The University of Texas Health Science Center at Houston
Department of Microbiology and Molecular Genetics
- Host-pathogen interactions
- Gene regulation
- Microbial toxins
Bacillus anthracis, a Gram-positive spore-forming soil bacillus and member of the Bacillus cereus group species, is distinguished by its ability to cause lethal anthrax disease in mammals, including humans. Depending upon the route of entry of B. anthracis spores, infection can result in cutaneous lesions, which are readily treatable with antibiotics, or systemic lethal disease, which is often fatal. Once a devastating disease of domestic livestock, improvements in environmental hygiene and immunization of livestock have contributed to a global decline of anthrax. However, the continuing worldwide incidence of anthrax in animal populations, the risk of human infection associated with animal outbreaks, and the potential for use of B. anthracis as a biological weapon, warrant continued investigation of this organism and its virulence mechanisms.
Virulence of B. anthracis is associated with synthesis of the anthrax toxin proteins, protective antigen, lethal factor, and edema factor, and an antiphagocytic capsule composed of poly-D-glutamic acid. Work in our laboratory is focused on the genetic basis for expression of the structural genes for the toxin proteins, pagA, lef, and cya, the capsule biosynthesis operon, capBCADE, and other genes with a known or suspected role in virulence. The toxin genes are located on the 182-kb plasmid pXO1, while the capsule genes are found on the 93-kb plasmid pXO2. The model for virulence gene regulation in B. anthracis is of growing complexity and includes numerous trans-acting regulators on the plasmids and the chromosome. The most critical and far-reaching regulator is atxA, a pXO1 gene that appears to be unique to B. anthracis. atxA is essential for expression of all three toxin genes, contributes to control of the capsule operon, and affects expression of numerous chromosomal genes. We are establishing the molecular functions and epistatic relationships of atxA and other regulators. The significance of atxA and other regulators in a mouse model for inhalation anthrax is also being assessed. In addition to transcriptional profiling studies, we are evaluating development of B. anthracis infection in the mouse model, including spacial and temporal measurements of germination and dissemination.
In related work, we are examining the relatedness of B. anthracis to the closely-related, but less harmful Bacillus cereus group species, B. cereus and B. thuringiensis. These species are very similar physiologically and genetically, yet they cause vastly different diseases. With certain important exceptions, key differences in gene expression, as opposed to genetic content, may result in the ability of these species to cause vastly different diseases. We are investigating species-specific mechanisms for control of genes common to all of these species.
Finally, we are also interested in the B. anthracis lifecycle outside of the mammalian host. We are studying the ability of B. anthracis to germinate and multiply in the soil, particularly in association with the plant rhizosphere, as has been documented for B. cereus. These investigations have implications for genetic exchange between B. anthracis and other soil organisms and for detection of the bacterium in the environment.
Ross, C.L., Thomason, K.S., and Koehler, T.M.: An Extra-Cytoplasmic Function Sigma Factor Controls b-lactamase Gene Expression in Bacillus anthracis and other B. cereus group species. J. Bacteriol. 191:6683-6693. 2009.
McGillivray, S.M., Ebrahimi, C.M., Fisher, N., Sabat, M., Chen, Y., Haste, N.M., Aroian, R.V., Gallo, R.L., Guiney, D.G., Friedlander, A.M., Koehler, T.M., and Nizet, V.: ClpX protease promotes Bacillus anthracis virulence through evasion of host antimicrobial peptide defense. J. Innate Immun. 1:494-506. 2009. Cited by Faculty of 1000.
Chand, H.S., Drysdale, M., Lovchik, J., Koehler, T.M., Lipscomb, M.F., Lyons, C.R.: Discriminating virulence mechanisms among &Bacillus anthracis strains by using a murine subcutaneous infection model. Infect Immun. 77:429-35. 2009.
Barua, S., McKevitt, M., DeGuisti, K., Hamm, E.E., Larabee, J., Shakir, S., Bryant, K., Koehler, T.M., Blanke, S.R., Dyer, D., Gillaspy, A., Ballard, J.D.: The Mechanism of Bacillus anthracis Intracellular Germination Required Multiple and Highly Divergent Genetic Loci. Infect. Immun. 77:23-31. 2009.
Lisanby, M.W., Swiecki, M.K., Pflughoeft, K.J., Koehler, T.M., and Kearney, J.F.: Cathelicidin administration protects mice from Bacillus anthracis spore challenge. J. Immunol. 181:4989-5000. 2008.
Program in Microbiology and Molecular Genetics