William R. Bishai, M.D., Ph.D.
William Bishai’s research focuses on understanding how and why Mycobacterium tuberculosis, the bacteria that causes tuberculosis (TB), has been so successful at infecting humans. Specifically, his laboratory uses genetic techniques to investigate how M. tuberculosis can slip under the radar of the human immune system. Bishai and his colleagues have learned that the microbe has developed a range of clever strategies to foil macrophages—immune system cells that attack and engulf invaders. Understanding the fundamental interactions that occur between the microbe and human cells is a critical step in developing new drugs or vaccines to treat tuberculosis, and Bishai plans to use the same strategy at K-RITH to develop new quicker, cheaper tools for diagnosing TB infection.
My research focuses on understanding the pathogenesis of tuberculosis (TB) and working to control TB by seeking improved biomarkers, diagnostics, and drugs.
Mycobacterium tuberculosisis 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. Considerable effort by my group has contributed to understanding 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. Through studying the mouse, guinea pig, and rabbit models of TB, which require extensive containment facilities, we have focused upon 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 the microbe 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. programmes 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.
K-RITH Director, 2010-Present
Johns Hopkins University professor and co-Director, Center for TB Research
- B.A., biochemistry, Harvard College
- M.Phil, pharmacology, Cambridge University
- M.D/Ph.D., microbiology and molecular genetics, Harvard Medical School
- Diplomate in Internal Medicine, American Board of Internal Medicine, 1992
- Diplomate in Infectious Diseases, American Board of Internal Medicine, 1994, 2004
- Co-Chair, WHO Stop-TB Partnership Working Group for New Drugs.
- The Gardner Middlebrook Award, Becton Dickinson
- Member, American Society for Clinical Investigation
- Joseph Bates Young Investigator Award, American Lung Association/American Thoracic Society
- Howard Hughes Postdoctoral Research Fellowship for Physicians
- The Mycobacterium tuberculosis protein Ldt(Mt2) is a nonclassical transpeptidase required for virulence and resistance to amoxicillin. Nature Medicine
- Cyclic AMP intoxication of macrophages by a Mycobacterium tuberculosis adenylate cyclase. Nature
- Penitentiary or penthouse condo: the tuberculous granuloma from the the microbe’s point of view. Cell Microbiology
- Bacterial thymidine kinase as a non-invasive imaging reporter for Mycobacterium tuberculosis in live animals. PLoS One
- Extensively drug-resistant tuberculosis. Lancet Infectious Diseases
- Shih-Jung Pan, JHU Post-Doctorate
- Emily Wong, JHU Post-Doctorate
- Keira Cohen, JHU Post-Doctorate
- Uvi Naidoo, Research Associate
- Prudy Seepe, PhD Student
- Hui Yang, JHU Research Intern
- Eamon Duffy, Research Intern
- Zuri Sullivan, Fullbright Scholar
- Chivonne Moodley, Laboratory Technologist, firstname.lastname@example.org
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