Biomedical Sciences Graduate Program | University of California, San Francisco

Bacterial pathogens have evolved elaborate schemes to evade, resist, or debilitate the mammalian immune system in order to survive within the host. Furthermore, disease caused by these pathogens is influenced not only by the bacterium but also by the host's immune response. We are interested in understanding the molecular details of the relationship between host and pathogen that are responsible for tuberculosis (TB), the leading cause of death worldwide due to infectious disease. To begin to ask questions about TB pathogenesis, we have taken a molecular genetic approach to identify virulence genes of Mycobacterium tuberculosis, the causative agent of TB. Initial results suggest that M. tuberculosis employs a number of unique mechanisms that make it a highly virulent and persistent pathogen.

In accordance with its aerosol route of transmission, M. tuberculosis has evolved a marked tropism for growth in lung tissue. Using a powerful genetic screen for attenuated M. tuberculosis mutants, we have isolated a number of strains that are avirulent in the lungs of infected mice but fully virulent in other organs. Many of these mutants are defective in the production or secretion of an unusual polyketide, termed PDIM, which is found only in virulent mycobacteria. Our current research focuses on how PDIM interacts with host cells and how it endows lung-specificity to the microbe.

Another unique aspect of M. tuberculosis pathogenesis is the organismÕs ability to cause a latent, persistent infection that can reactivate to cause active disease years after the initial infection. Using new genetic and genomic tools, we are searching for genes that are critical for persistence in the mouse model of TB to address the question of how M. tuberculosis survives in the host during robust immune responses.

Our long-term research goals are to identify M. tuberculosis molecules important for virulence or persistence and to understand the role they play in the complex interactions between prokaryote and eukaryote. Ultimately, by understanding the details of TB pathogenesis at the molecular level, we hope to identify molecules that interfere with critical host-pathogen interactions that will aid in the discovery of new therapies to combat and eradicate this persistent infection.