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Title: Regulation of cellular immunity by human cytomegalovirus
Author: Patel, Mihil
ISNI:       0000 0004 7426 6784
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2018
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The success of HCMV as a lifelong pathogen is attributed at least in part to the broad range of encoded immune evasion molecules that inhibit the host cellular immune response. Indeed, HCMV has become a paradigm for immune evasion, the study of which has revealed a number of basic immunological processes. To screen for novel immune evasion genes, HCMV-specific CD8+ T-cell lines were grown from seropositive donors and used against a series of block deletion viruses, each missing a region of genes non-essential for replication in vitro. UL13-UL20 was flagged as important for inhibition of CD8+ T-cells. Further screening with individual gene knockout HCMVs showed that the published NK-cell inhibitor UL16 could inhibit CD8+ T-cells, but also revealed UL19 as a previously unrecognised strong immune evasin, inhibiting 3 separate CD8+ T-cell lines. UL19 had no effect on HLA-I downregulation indicating that it may affect other pathways involved with T-cell activation. Proteomic data showed that surface TNFR2 was increased by HCMV infection. This is important as this would influence the response to TNF, a major inflammatory cytokine and soluble effector molecule released by T and NK cells. Screening using different HCMV strains and knockout viruses identified UL148 and UL148D as responsible for the increase in surface TNFR2 but prevented the release of soluble TNFR2, indicating that UL148 and UL148D were influencing the ability of TNFR2 to be retained at the cell surface. Infection with HCMV Merlin profoundly downregulated surface ADAM17, the metalloproteinase responsible for cleaving TNFR2 from the cell surface. Deleting UL148 and UL148D recovered ADAM17 expression, blocking the function of which returned surface and soluble TNFR2 levels to those observed with Merlin. This was also true of TNFR1. HCMV infected cell lysates showed that UL148 and UL148D interfered with the maturation of ADAM17. Thus, UL148 and UL148D allow upregulation of TNFR2 and maintain TNFR1 expression during and HCMV infection by impairing surface ADAM17 expression through impairment of ADAM17 maturation. Given that ADAM17 is involved with the cleaving of multiple cytokines, cytokine receptors, adhesion molecules and immune cell receptors, this work identifies a novel mechanism through which HCMV can alter the surface and soluble proteome by preventing the shedding of inflammatory/immune receptors and mediators. More detailed studies will be required to define the global impact of this on the immune system.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available