The overall goal of our research is to understand the molecular and cellular basis of microbial pathogenesis and the mechanisms used by the host to defend against infection. Specifically, the lab is focused on the interaction of the facultative intracellular bacterial pathogen Listeria monocytogenes and mammalian cells. This fascinating microorganism is able to enter cells, escape from a phagosome and grow rapidly in the cytosol. By exploiting a host system of actin-based motility, the bacteria move through the cytosol to the cell membrane and into pseudopod-like projections (listeriopods) that are ingested by neighboring cells. This mechanism allows pathogens to spread from one cell to another without ever leaving the host cytoplasm thereby avoiding the immune response.
Cell biology of infection. The primary L. monocytogenes determinant responsible for lysis of host cell vacuoles is the pore-forming cytolysin, listeriolysin O (LLO). We will continue to focus on the control of LLO synthesis and secretion, and its mechanism of action. The ultimate goal is to relate structural and biochemical information to its precise mechanism of action in both tissue culture and in mice. We are also characterizing a number of fail-safe mechanisms that prevent LLO toxicity in the host cytosol and thereby compartmentalize its activity to acidic vacuoles. Interestingly, mutants that fail to properly compartmentalize LLO activity are cytotoxic to infected host cells and attenuated for virulence in mice. The L. monocytogenes ActA protein is necessary and sufficient to mediate actin-based motility in cells and cell-freeextracts. Actin polymerization is controlled by interaction of ActA with the host Arp2/3 complex and members of the Ena/VASP family. During the next few years we will focus on the mechanism of ActA function and evaluate its role during infection.
Immunity to infection. Murine listeriosis is an outstanding model to study basic aspects of innate and acquired cell-mediated immunity. Using bacterial mutants blocked at various stages in the infection process, we are elucidating pathways of host cell gene expression in response to microbial infection. Our studies clearly document the presence of a vacuolar and cytosolic pathway of innate immune recognition. Using bacterial genetics and biochemistry, we identified a secreted bacterial molecule (c-di-AMP) that activated a host pathway of innate immunity.
In the News
UC Berkeley cancer immunologists are teaming up with colleagues working on infectious disease to create a new Immunotherapeutics and Vaccine Research Initiative.
In recognition of their excellence in original scientific research, three UC Berkeley faculty members have been elected members of the National Academy of Sciences (NAS), one of the highest honors given to a scientist or engineer in the United States.
In a 20-year quest to determine why Listeria bacteria produce a uniquely strong immune response in humans, UC Berkeley scientists have found part of the answer: an unsuspected signaling molecule that the bacteria pump out and which ramps up production of interferon by the host. Interferon mobilizes the immune system to fight off bacteria and viruses.