Characterization of the innate immune response to human cytomegalovirus infection

Innate immunity is a critical component of the global host response to viral infection. Effective containment and clearance of viruses is dependent upon the appropriate and timely responses of this branch of the immune system. In spite of its importance, the mechanisms by which the innate immune system responds to viral infection have only begun to be elucidated. The work presented in this thesis aims to identify and characterize host factors involved in the innate immune response to human cytomegalovirus (HCMV), a ubiquitous member of the herpesvirus family and an opportunistic pathogen that poses a significant health risk for immunocompromised patient groups. It is now well appreciated from the work of many laboratories that HCMV elicits a strong innate response upon infection, characterized by NF-kappaB activation, inflammatory cytokine secretion, and induction of the interferon pathway. Previous studies demonstrated that envelope glycoprotein B (gB) is a component of the HCMV virion that induces interferon-stimulated gene (ISG) expression. Chapter 2 further characterizes the responses initiated by HCMV and gB and demonstrates that gB induces phosphorylation and nuclear localization of a key cellular transcription factory, interferon-regulatory factor 3, which in turn leads to the production of interferon-beta. The physiological consequence of these responses to HCMV and gB is the establishment of an antiviral state within cells. The ability of gB to elicit these responses indicates that HCMV activates innate immunity via interactions between viral envelope glycoproteins and receptors on the surface of the cell. Chapter 3 describes the initial discovery that Toll-like receptor 2 (TLR2) and CD14 serve as cell surface receptors that recognize and initiate innate responses to HCMV virions. Chapter 4 extends the studies from Chapter 3 into cells that are biologically relevant for HCMV infection. TLR2 is expressed by HCMV-permissive human fibroblasts and mediates inflammatory cytokine responses and NF-kappaB activation in these cells. Furthermore, gB and gH are identified as ligands for TLR2. Together these studies further elucidate the mechanisms by which HCMV activates host innate immunity and may contribute to the development of effective vaccines and therapeutics.