Current Research and Scholarly Interests
Over the most recent decade my laboratory has focused on the infected cell response to infection, mainly the contribution of regulated cell death pathways to host defense. The phenomenal diversity of CMV-encoded modulators of the host response to infection provided an opening, with the cell death suppressors, which have been conserved in human and murine CMV, evolved as separate pathogens, contributing handily to the knowledge base. We recently discovered that caspase 8 can be eliminated from the mouse germ line, most likely because this protease evolved in mammals under the adaptive pressure of large viruses that encode suppressors of mitochondrial apoptosis. Our characterization of receptor interacting protein (RIP)3 kinase-dependent programmed necrosis as a trap door that opens when caspase 8 activity is compromised points to a multi-level and complementary contribution of programmed cell death pathways to host defense. These efforts show that CMV-encoded viral inhibitor of caspase 8 activation (vICA) and viral inhibitor of RIP activation (vIRA) block caspase-dependent apoptosis and RIP3-dependent necrosis, respectively. In the absence of vIRA, the pathogen sensor DAI senses input viral DNA and then oligomerizes with RIP3 to initiate programmed necrosis that eliminates infected cells. We have established that vICA suppression of caspase 8 activity is an essential part of this process, and that, together, vICA and vIRA represent key modulators of potent host defense pathways. These insights prompted our discovery that embryonic lethality due to germline deficiency in caspase 8 results from dysregulated RIP3 kinase-dependent necrosis. Because CMV is such a master manipulator of the host response to infection, other individual viral gene products have provided us with high impact observations, such as the virus-encoded chemokine whose function assures CMV-susceptible myeloid cells are recruited to sites of infection as vehicles for dissemination as well as to downmodulate the CD8 T cell response to infection. My research interests continue to be in CMV replication functions, characterization of the latent CMV reservoir in myelomonocytic progenitors, dissection of immunomodulatory pathways including the cellular response to viral infection as well as our most recent mechanistic studies focused on complementary and overlapping viral and host pathways.
