David Sherman's work is focused on tuberculosis (TB) virulence and drug discovery. TB takes at least six months to treat, and the bacterium responsible has developed widespread resistance to the currently available drugs, so there is a great need for new therapies.

Research

With about one-third of the world’s population infected and two million deaths caused each year, 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. Sherman is 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 percent 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 models to test this idea were inadequate. To address this gap, the Sherman lab has developed methods to maintain M. tuberculosis for extended periods in defined microaerophilic environments. Using this system, lab members 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. They are performing detailed molecular characterization of hypoxic signal transduction and DosR activation. In addition, they have extended their studies to characterize the mycobacterial response to longer term hypoxia, and to subsequent reaeration, which may serve as a model of reactivation.

The Sherman Lab is also engaged in detailed analyses of M. tuberculosis gene expression in vitro and in vivo, and has developed a novel approach to study bacterial replication rate during infection. Lab members maintain a longstanding interest in what the TB vaccine BCG and other attenuated mutants can reveal about mycobacterial virulence. In addition, the lab is interested in molecular mechanisms that may explain why TB treatment requires at least six months of chemotherapy.

The Sherman Lab also focuses on novel assays and targets for much-improved anti-TB drugs. Lab members routinely employ a variety of research tools, including molecular genetics (targeted gene disruption, conditional gene expression, TraSH), biochemistry, cultivation in vitro, in macrophages and in various animal models, and whole genome microarray analysis.

Support for Sherman’s work is provided by the National Institutes of Health, the Paul G. Allen Family Foundation, and the Bill and Melinda Gates Foundation.

Biography

Education

Ph.D.    Biochemistry    Vanderbilt University

A.B.      Zoology           University of California, Berkeley

Professional Experience

• Director, Tuberculosis Program, Seattle Biomedical Research Institute, 2007 - present
• Full Professor, Seattle Biomedical Research Institute, 2009 - present
• Member, Pathobiology Graduate Program, Department of Global Health, University of Washington School of Public Health and Community Medicine, 2008 - present
• Affiliate Associate Professor, Department of Global Health, University of Washington School of Public Health and Community Medicine, 2007 - present
• Associate Member, Seattle Biomedical Research Institute, 2007 - 2009
• Associate Professor, Pathobiology Department, University of Washington School of Public Health and Community Medicine, 2004 - 2008
• Assistant Professor, Pathobiology Department,
  University of Washington School of Public Health and Community Medicine, 1998 - 2004
• Senior Scientist, Department of Research Biology, PathoGenesis Corporation, 1994 - 1998
• Research Assistant Professor of Medicine and Molecular Microbiology, Washington University School of Medicine, 1991 - 1993
• Postdoctoral Fellow, The Rockefeller University, 1988 - 1991
  Select Honors and Awards
• American Institute of Nutrition, Proctor and Gamble Award for Excellence in Graduate Student Research, 1987
• Samuel Roberts Noble Fellow, 1985-1987
• Harold Stirling Vanderbilt Scholar in Biochemistry, 1982-1987
• Regents Scholar of New York, 1976-1978

Field of Study

I have always looked for my work to be four things: fun, interesting, challenging and useful. TB is one of the world’s great neglected diseases, but it is also one of the world’s great biological puzzles. I love working with very talented people the world over to tackle challenging and important biological problems.

Publications

Accomplishments & Collaborations

Accomplishments

• Helped to define the molecular and biochemical response of M. tuberculosis to oxidative stress and to drugs such as isoniazid.
• Developed methods to maintain M. tuberculosis for extended periods in defined microaerophilic environments.
• Identified and characterized the M. tuberculosis response to reduced oxygen tension.
• Defined and characterized the molecular lesion responsible for attenuation of the TB vaccine, M. bovis BCG, which has been given to billions of people worldwide.

Collaborations

• University of Washington
• Infectious Disease Research Institute
• Harvard University
• National Institutes of Health
• Stanford University
• University of Cambridge
• Imperial College, London
• University of Witwatersrand, Johannesburg