Current Research and Scholarly Interests
The laboratory has focused on the infected cell response to infection, mainly the contribution of regulated cell death pathways to host defense against viruses. A mechanistic understanding of cytomegalovirus (CMV)-encoded modulators of cell death enabled the discovery of alternate cell death pathways that are active in mammals. All large mammalian DNA viruses encode multiple suppressors of apoptosis that have been shown to play out via mitochondrial components or via cytosolic cell death machinery. Cell death suppressors encoded by human CMV are conserved in murine CMV. Direct studies of this species restricted virus in infected mice have helped to provide information on the natural role these suppressors play in human CMV pathogenesis. After identifying the CMV-encoded viral inhibitor of mitochondrial apoptosis (vMIA) and characterizing the caspase-independent cell death pathway that this suppressor blocked during infection, we described a second player, the CMV-encoded viral inhibitor of caspase 8 activation (vICA), capable of suppressing extrinsic apoptosis and necessary for either human or murine CMV replication in macrophage lineage cells from the respective species. A third cell death suppressor, viral inhibitor of receptor interacting protein RIP activation (vIRA) unvealed a second caspase-independent pathway, programmed necrosis. Suppression of caspase-8 activity by vICA unleashed this alternative (trap door) necroptosis, a pathway that is triggered by Z-nucleic acid binding protein (ZBP)1, mediated by RIPK3 and executed by a protein called mixed lineage-like (MLKL). The pathogen sensor ZBP1 (also called DAI) senses newly synthesized viral RNA, oligomerizes with RIPK3, and the murine CMV-encoded vIRA prevents this recruitment and oligomerization. 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. Through such investigations discovered that developmental death of caspase 8-deficient and receptor-interacting protein kinase (RIPK)1-deficient mice is due to alternate cell death pathways controlled by RIPK3 that evolved to control intracellular pathogens such as viruses. We were the first laboratory to demonstrate the importance of RIPK3-dependent necroptosis in innate host resistance to viral infection through the elaboration of necroptosis inhibitors encoded by CMV, herpes simplex virus and the poxvirus, vaccinia. This work has highlighted the importance of ZBP1 as a specialized pathogen sensor triggering RIPK3-dependent cell death and inflammatory pathways. We further demonstrated that mice lacking caspase-8 and RIPK3 as well as mice lacking RIPK1 caspase-8 and RIPK3 mount a robust immune response that controls virus infection despite the absence of cell death, attributed to the ability of other cell death-dependent and cell death-independent host defense pathways to control viral infection. 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.
