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Understanding the pathogenesis of Mycobacterium tuberculosis
Summary: William Bishai's research focuses on understanding the pathogenesis of tuberculosis (TB) and working to control TB by seeking improved biomarkers, diagnostics, and drugs.
Mycobacterium tuberculosis is a highly human-adapted pathogen. The microbe subverts the human innate immune system and acquired immunologic clearance mechanisms in order to maintain its own long term survival. I have been working to understand the regulatory pathways M. tuberculosis uses to detect its environment and activate response pathways that enable its survival. Microbial sigma factor networks, as well as an unusual iron-sulfur cluster binding regulator family (the WhiB-family regulators), contribute significantly to M. tuberculosis virulence upon entry into the human host. Usingthe mouse, guinea pig, and rabbit models of TB, my lab has identified some of the genetic requirements in M. tuberculosis that enable the formation of necrotic, caseating granulomas and cavitary granolumas (unique to the rabbit model). One important observation was that the loss of key regulatory genes in the microbe, such as certain RNA polyermase sigma factors, reduces the inflammation seen in animal infections but does not reduce the ability of the microbe to proliferate. Also, we have found that M. tuberculosis generates copious amounts of the second messenger cyclic AMP (cAMP), which is secreted into host cells thereby subverting eukaryotic signalling and generating altered inflammatory responses.
Our work on drugs and biomarkers has led to the advancement of several novel anti-TB drug regimens including the observation that moxifloxacin is a key anti-TB drug that may be capable of replacing isoniazid in the treatment of TB. Additionally, through the availability of a large M. tuberculosis mutant collection generated at Johns Hopkins, we have found that peptidoglycan-modifying enzymes govern susceptibility to beta-lactam antibiotics and may comprise a family of exciting novel drug targets.
Research at K-RITH will extend our lab’s ability to identify improved drug regimens and biomarkers through the close proximity of patients with active tuberculosis. Programs are currently in place to study the early bactericidal activity of novel anti-TB drug regimens and the activity of metabolomic biomarkers, such as the urea breath test with TB patients in KwaZulu-Natal.
As of May 30, 2012
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