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The Role of Human Cytomegalovirus-Encoded G Protein-Coupled Receptors During Viral Infection

Dooley, Abigail L
http://orcid.org/0000-0002-5106-1722
http://rave.ohiolink.edu/etdc/view?acc_num=case1689189772176015

Abstract Details

2023, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus residing latently in a majority of the population. While generally asymptomatic in healthy individuals, primary infection or reactivation of latent infection in the immunocompromised, immunosuppressed, and immunonaïve can lead to end organ failure if left untreated. HCMV encodes four G protein-coupled receptors (GPCRs), which play roles in both lytic and latent infection by manipulating the host cell environment, in some cases through altering cell signaling. The objective of these studies was to gain further insight into the role the HCMV-encoded GPCRs, US28 and UL33, play in the molecular mechanisms of lytic and latent infection, and in turn viral dissemination and transmission. In the first study, we demonstrate a new mechanism by which US28 controls HCMV latency. Our lab previously showed US28 is necessary for the establishment and maintenance of HCMV latency. To gain a more complete understanding of the cellular factors US28 manipulates during latency, we evaluated cellular transcriptomic changes in response to US28 expression and found this viral GPCR upregulates the cellular gene, myeloid nuclear differentiation antigen (MNDA). Previous findings revealed MNDA increases DNA-binding of the cellular transcription factor, Yin Yang 1 (YY1), which is a repressor of the major immediate early (MIE) enhancer/promoter, a region whose regulation of immediate early gene expression, in part, controls the balance between HCMV latency and reactivation. We show US28 upregulates MNDA, leading to a US28-dependent interaction between MNDA and YY1. This complex binds the MIE enhancer/promoter, resulting in transcriptional silencing of this locus, thereby aiding in the maintenance of latent infection. These studies reveal a new mechanism by which US28 regulates the MIE enhancer, through the control of cellular proteins MNDA and YY1. Secondly, we evaluated the HCMV-encoded GPCR UL33 and its role in viral replication. Previous studies showed UL33 is dispensable for lytic infection in fibroblasts, however the role of UL33 in cell types required for viral dissemination and transmission, such as epithelial cells, remains unknown. Rodent homologs of HCMV UL33, murine CMV M33 and rat CMV R33, play an important role in viral pathogenesis in their respective hosts, as deletion of these homologs leads to a replication defect in salivary gland epithelial cells in their respective species. To determine if UL33 plays a similar role in HCMV infection of epithelial cells, we evaluated the impact of UL33 on lytic replication in epithelial cells. In our studies, we found UL33 is required for efficient viral growth, as well as viral mRNA and viral protein expression in epithelial cells. Further, we determined UL33 is required for efficient binding of the HCMV virion to epithelial cells, which in turn leads to decreased entry and virion delivery. These studies suggest the HCMV-encoded GPCR, UL33, is important for efficient lytic replication in epithelial cells.
Christine O'Connor, Ph.D. (Advisor)
Robert Silverman, Ph.D. (Committee Chair)
Michelle Longworth, Ph.D. (Committee Member)
Robert Fairchild, Ph.D. (Committee Member)
Christine Koval,, M.D. (Committee Member)
247 p.
Biology; Microbiology; Virology
Human cytomegalovirus; viral infection; virology; G protein-coupled receptors; transcriptional repression; viral entry

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Citations

  • Dooley, A. L. (2023). The Role of Human Cytomegalovirus-Encoded G Protein-Coupled Receptors During Viral Infection [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1689189772176015

    APA Style (7th edition)

  • Dooley, Abigail. The Role of Human Cytomegalovirus-Encoded G Protein-Coupled Receptors During Viral Infection. 2023. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1689189772176015.

    MLA Style (8th edition)

  • Dooley, Abigail. "The Role of Human Cytomegalovirus-Encoded G Protein-Coupled Receptors During Viral Infection." Doctoral dissertation, Case Western Reserve University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=case1689189772176015

    Chicago Manual of Style (17th edition)

case1689189772176015
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© 2023, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12