: Central to the pathogenic success of Mycobacterium tuberculosis (MTB) is its ability to persist within humans for long periods in a latent state, without causing any overt disease symptoms. Roughly one-third of the world population harbors latent MTB, greatly complicating efforts at tuberculosis control. A person with latent tuberculosis has about a 10 percent lifetime chance of developing active disease, and when such a person contracts HIV, the risk of developing reactivation TB increases to 8 - 10 percent per year. Hypoxic conditions within the human host are widely regarded as crucial for development of latent tuberculosis, but the MTB adaptive response to hypoxia is at present very poorly understood. The goal of this proposal is to define the MTB hypoxic response as it relates to latency and reactivation. We will mechanistically dissect this response and analyze the role of hypoxia in latent tuberculosis and reactivation. This proposal will define the genes whose response to reduced oxygen tension comprises the MTB hypoxia regulon. We will also focus on MTB alpha-crystallin (Acr), a component of the hypoxic response that is powerfully induced by microaerophilic conditions. We will determine the specific conditions in which expression of alpha-crystallin and its regulators is necessary for achieving latency or reactivation. Finally, we will dissect the alpha-crystallin regulatory machinery to determine the precise mechanisms by which oxygen tension controls MTB gene expression. The result will be better tools to confront the threat to more than one billion persons with latent tuberculosis, millions of whom are now or will soon be co-infected the the human immunodeficiency virus, HIV.
| Gill, Wendy P; Harik, Nada S; Whiddon, Molly R et al. (2009) A replication clock for Mycobacterium tuberculosis. Nat Med 15:211-4 |
| Rustad, Tige R; Roberts, David M; Liao, Reiling P et al. (2009) Isolation of mycobacterial RNA. Methods Mol Biol 465:13-21 |
| Roberts, David M; Liao, Reiling P; Wisedchaisri, Goragot et al. (2004) Two sensor kinases contribute to the hypoxic response of Mycobacterium tuberculosis. J Biol Chem 279:23082-7 |
| Park, Heui-Dong; Guinn, Kristi M; Harrell, Maria I et al. (2003) Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis. Mol Microbiol 48:833-43 |
| Sherman, D R; Voskuil, M; Schnappinger, D et al. (2001) Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding alpha -crystallin. Proc Natl Acad Sci U S A 98:7534-9 |
