The Shiloh laboratory is broadly interested in how M. tuberculosis is able to establish a latent infection in humans. We have previously shown that when M. tuberculosis infects macrophages, the host enzyme heme oxygenase is induced both in vitro and in vivo (Figure 1). Heme oxygenase produces carbon monoxide gas, and M. tuberculosis respond to host CO gas by inducing genes involved in establishing a latent infection. Interestingly, M. tuberculosis is resistant to the toxic effects of CO gas. We screened a transposon library for mutants unable to grow in the presence of CO, and have identified a mutant that fails to grow in the presence of CO (Figure 2). This mutant is attenuated in vivo, confirming the importance of its gene product for pathogenesis. We are currently in the process of characterizing its function, as well as identifying other CO resistance genes.

In another project, we are characterizing M. tuberculosis essential focusing on genes that are annotated as genes of unknown function. Using a combination of bioinformatics, molecular biology and biochemistry, we are identifying novel functions. Eventually, we anticipate screening chemical libraries in the UT Southwestern high throughput core facility for inhibitors of essential genes that might serve as new anti-tuberculous drugs.