Manipulation of the Immune Response by Human Cytomegalovirus

Abstract

Human cytomegalovirus (HCMV) is an endemic betaherpesvirus whose persistence can be attributed to evasion of the immune response. The intrinsic immune response, the first to be activated, is mediated by endogenously expressed antiviral proteins. The core proteins of Nuclear Domain 10 (ND10) - Promyelocytic leukemia factor (PML), speckled protein of 100kDa (Sp100) and human death domain associated protein 6 (hDaxx) - are key effectors of the intrinsic response to HCMV. This thesis demonstrates that PML and Sp100 are upregulated by type I interferons (IFNs) during HCMV infection and that this contributes significantly to the antiviral capacity of type I IFNs. Type I IFNs are proinflammatory cytokines produced during the innate immune response to HCMV. Type I IFNs induce an antiviral state by upregulation of IFN stimulated genes (ISGs). This thesis explores IFN-independent regulation of ISGs by HCMV, using cell lines lacking the ability to produce or respond to IFNs. The ISGs identified as being regulated independently of IFN are: IFIT1, IFIT2, IFIT3, ISG15, CXCL10, Mx1 and Mx2.

The antigen presenting molecule, major histocompatibility complex class I (MHC) I is also an ISG. Levels of MHC I and MHC I-like molecules are extensively regulated by HCMV. Therefore, this thesis explored the regulation of MHC I related molecule 1 (MR1) that had not previously been studied during HCMV infection. Although MR1 was not an ISG, its expression was regulated by HCMV. In the absence of exogenous MR1 ligand, HCMV infected cells upregulated MR1 cell surface expression, while in the presence of MR1 ligand, HCMV infection impaired MR1 cell surface expression. Some ligands bound by MR1 activate innate-like mucosal-associated invariant T (MAIT) cells. To date, MR1-dependent activation of MAIT cells is known to protect against bacterial and fungal pathogens. In the context of viral infection, MAIT cells can be activated in an MR1-independent manner by proinflammatory cytokines. However, this thesis demonstrates that HCMV infection can inhibit MR1-dependent MAIT cell activation, a finding suggests HCMV could alter the pathogenesis of bacterial or fungal co-infections. This thesis also raises the possibility that HCMV-associated MR1 ligands exist, and that MAIT cells may play a role in monitoring HCMV infection.