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RESEARCH INTERESTS

Escape from a vacuole and cell to cell spread of L. monocytogenes. The stippled material depicts F-actin.

 

Dr. Portnoy's lab is focused on the microbiology and immunology of infections caused by intracellular pathogens. Specifically, the laboratory works on the facultative intracellular pathogen, Listeria monocytogenes: a Gram-positive, rapidly growing pathogen of animals and humans that has been used for decades as a model pathogen to explore basic aspects of both infection and immunity. The laboratory works on a number of overlapping areas including an in-depth dissection of Listeriolysin O (LLO), an essential determinant of L. monocytogenes pathogenesis. LLO allows bacteria to escape from a phagosome so that they can grow rapidly in the host cell cytosol. LLO is regulated at the transcriptional, translational, and post-translational levels providing many avenues of research. Recently, students in the lab performed a saturating and comprehensive genetic screen for bacterial mutants that were defective in expression of LLO and found many new components involved in its expression, secretion and function.

The laboratory is also interested in innate immune pathways triggered by L. monocytogenes. Three distinct pathways are being characterized; one that emanates from a phagosome, one that emanates from the cytosol leading to the host's expression of interferon, and a third pathway that leads to inflammasome activation. Genetic screens are being performed to identify mutants that activate both enhanced and diminished responses. Again, numerous genes have been identified. For example, mutants that overexpress bacterial multidrug efflux pumps induce 20-times more interferon. These and related studies are part of an NIH-sponsored program project grant with other Bay Area investigators to explore the interactions of five different intracellular pathogens and macrophage innate immune responses.

L. monocytogenes induces a robust cell-mediated immunity. Consequently, it is being developed by the private sector as a live, attenuated, vaccine vector for both cancer and infectious disease applications where cell-mediated immunity is required. The Portnoy lab is exploring the capacity of mutants described above to induce acquired immunity.

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