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.