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David Sherman, Ph.D.
Full Professor, Seattle Biomedical Research Institute
Adjunct Associate Professor , Department of Global Health, University of Washington
Area of Expertise: tuberculosis, drug discovery, systems biology
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.
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.
Ph.D. Biochemistry Vanderbilt University
A.B. Zoology University of California, Berkeley
- 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.
Bioinformatic and Empirical Analysis of Novel Hypoxia-Inducible Targets of the Human Antituberculosis T Cell Response
High-throughput Screening and Sensitized Bacteria Identify an M. tuberculosis Dihydrofolate Reductase Inhibitor with Whole Cell Activity
The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection
Pathway profiling in Mycobacterium tuberculosis: elucidation of cholesterol-derived catabolite and enzymes that catalyze its metabolism
The polyketide Pks1 contributes to biofilm formation in Mycobacterium tuberculosis Pks1 and TB biofilms
Immune Responses to the Enduring Hypoxic Response Antigen Rv0188 Are Preferentially Detected in Mycobacterium bovis Infected Cattle with Low Pathology
Hypoxia Induces an Immunodominant Target of Tuberculosis Specific T Cells Absent from Common BCG Vaccines
Characterization of a Clp Protease Gene Regulator and the Reaeration Response in Mycobacterium tuberculosis
A blind deconvolution approach to high-resolution mapping of transcription factor binding sites from ChIP-seq data
Trafficking of Superinfecting Mycobacterium into Established Granulomas Occurs in Mammals and is Independent of the Mycobacterial Erp and ESX-1 Virulence Loci
New classes of Gram-positive selective antibacterials: inhibitors of MRSA and surrogates of the causative agents of anthrax and tuberculosis
Crystal Structures of the Response Regulator DosR from Mycobacterium tuberculosis Suggest a Helix Rearrangement Mechanism for Phosphorylation Activation
Epitope-driven TB vaccine development: a streamlined approach using immuno-informatics, ELISpot assays, and HLA transgenic mice
Structures of Mycobacterium tuberculosis DosR and DosR-DNA complex involved in gene activation during adaptation to hypoxic latency
Mycobacterium tuberculosis H36Rv:ΔRD1 is more virulent than M. bovis BCG in long-term murine infection
Adenylylation and catalytic properties of M. tuberculosis glutamine synthetase expressed in E. coli vs. Mycobacteria
Individual RD1-region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis
Novel Saccharomyces cerevisiae screen identifies WR99210 analogues that inhibit Mycobacterium tuberculosis dihydrofolate reductase
Chetan Seshadri, visiting scientist
Jessica Winkler, lab assistant
John Szumowski, visiting scientist
Kyle Minch, postdoctoral fellow
Reiling Liao, senior research associate
Richard Wells, visiting scientist
Shuyl Ma, visiting scientist
Tige Rustad, senior scientist
Zdenek Spacil, visiting scientist
Accomplishments & Collaborations
- 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.
- 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