We use bacterial infection models to dissect molecular mechanisms for immune subversion and immune dysregulation. One aspect of our work focuses on understanding pathogenic strategies that microbes have evolved to thwart or manipulate immune responses. Another aspect is to understand host immune regulatory circuits that are manipulated by pathogens. We are interested in how each of these aspects impacts the ability pathogens to establish mucosal and systemic infections. We are also keenly interested in translating information from our studies into improved therapies for infectious, inflammatory, cancerous, and other diseases.
One current focus is on understanding the mechanisms by which specific bacterial proteins impact the activity of host innate immune cells, including macrophages, dendritic cells, and natural killer (NK) cells. We have identified a LysM-domain containing bacterial protein that triggers immune cell activation. We are interested in the mechanisms for such activation and in understanding how this immune activation benefits the pathogen. We are also interested in development of such immune activating factors for treatment of infections and cancers.
A second focus is on understanding the mechanisms and consequences of crosstalk between endogenous host cytokines. Cytokines such as type I interferons (IFN-ab) and interleukin 10 (IL-10) can suppress the activation of macrophages and other myeloid cells, and increase host susceptibility to a variety of bacterial infections. We are interested in how microbes induce production of these suppressive cytokines and how IFN-ab suppress myeloid cell activation. We recently found that IFN-ab reduce myeloid cell expression of receptors for activating cytokines such as IFNg. Additional mechanistic information on this process may be useful in developing host-directed therapies for infection and for improving the safety of IFN-ab based therapies for multiple sclerosis and other diseases.
The lab uses a variety of mouse models. Model pathogens include the bacteria Listeria monocytogenes and Francisella tularensis, both of which access and replicate in the cytosol of host phagocytes.