BACK

Research Description – David R. Sherman

With about one-third of the world population infected and two million deaths annually, Mycobacterium tuberculosis is unquestionably one of the world's most successful human pathogens. The Sherman laboratory studies the bacterial and host strategies that underpin this success.  We are especially interested in two formerly intractable areas of M. tuberculosis biology -- virulence and dormancy.  Since roughly two billion people are infected with M. tuberculosis worldwide but only about 1% of those people have active disease, factors that alter the balance between latency and illness are of great interest.  Dormant M. tuberculosis is thought to be associated with microaerophilic environments in the host, but current models to test this idea are inadequate.  To address this situation, we have developed methods to maintain M. tuberculosis for extended periods in defined microaerophilic environments.  Using this system. we have shown that the mycobacterial transcription factor DosR responds to a drop in oxygen tension by inducing expression of about 50 genes – the DosR regulon.  We are performing detailed molecular characterization of hypoxic signal transduction and DosR activation.  We are also engaged in detailed analyses of M. tuberculosis gene expression in vitro and in vivo, and have developed a novel approach to study bacterial replication rate during infection.  We maintain a longstanding interest in what the TB vaccine BCG and other attenuated mutants can tell us about mycobacterial virulence.  We are also interested in why TB treatment requires at least six months of chemotherapy.  We focus on novel assays and targets for much-improved anti-TB drugs and on understanding drug tolerance. We routinely employ a variety of research tools, including molecular genetics (targeted gene disruption, representational difference analysis, TraSH), biochemistry, cultivation in vitro, in macrophages and in various animal models, and whole genome microarray analysis.

Relevant publications:

• Sherman DR, Voskuil M, Schnappinger D, Liao RP, Harrell MI, Schoolnik GK: Regulation of the M. tuberculosis hypoxic response gene alpha-crystallin. Proc Natl Acad Sci USA, 2001, 98 (13): 7534-7539.
• Lewis KN, Liao R, Guinn KM, Smith S, Hickey, MJ, Behr MA, Sherman DR: Deletion of RD1 from M. tuberculosis mimics BCG attenuation.  J Inf Dis, 2003, 187: 117-123.
• Park HD, Guinn KM, Harrell MI, Liao R, Voskuil MI, Tompa M, Schoolnik GK, Sherman DR: Rv3133c/dosR is a transcription factor that mediates the hypoxic response of M. tuberculosis.  Mol Microbiol, 2003, 48(3):833-843.
• Guinn KM, Hickey MJ, Mathur SK, Zakel KL, Grotzke JE, Lewinsohn DM, Smith S, Sherman DR: Individual RD1-region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis.  Mol Microbiol, 2004, 51(2):359-370.
• Roberts DM, Liao RP, Wisedenchari G, Hol W, Sherman DR.  Two sensor kinases contribute to the hypoxic response of Mycobacterium tuberculosis.  J Biol Chem, 2004, 279:23082-7.
• Fortune SM, Jaeger A, Chase MR, Sarracino DA, Sassetti CM, Sherman DR, Bloom BR and Rubin EJ.  Mutually-dependent secretion of proteins required for mycobacterial virulence.  Proc. Natl. Acad. Sci, USA 2005, 102:10676-81.