Date of Graduation
Master of Science in Biology
College of Arts and Sciences
Dr. Juliet V. Spencer
Dr. John Sullivan
Dr. Christina Tzagarakis-Foster
Human cytomegalovirus (HCMV) is a widespread pathogen that causes lifelong latent infection. Successful persistence of HCMV in healthy individuals involves extensive manipulation of host cellular functions and immune responses. HCMV encodes four genes for putative G protein-coupled receptors (GPCRs): US27, US28, UL33, and UL78. The US28 gene product is a functional chemokine receptor that exhibits a variety of signaling outcomes. In contrast, the US27 gene product is an orphan with no known chemokine ligands. We have found that US27 triggers several biological effects: increased cellular proliferation, changes in gene expression, and enhanced signaling of cellular chemokine receptor CXCR4. Enhanced cell survival and proliferation were mediated by the DRY box and C-terminal domain (CTD) of US27. PCR array analysis revealed that expression of US27 led to up-regulation of pro-survival factor Bcl-x, AP-1 transcription factor components jun and fos, and down-regulation of cell cycle regulators CDKN1A (cyclin dependent kinase inhibitor 1A) and SESN2 (Sestrin2 or Hi95). These results indicate that increased cell proliferation due to US27 may be linked to suppression of negative growth regulators. In addition, US27 was shown to increase calcium mobilization of CXCR4 in response to its natural ligand CXCL12. cmvIL-10, an ortholog of human IL-10, was also found to enhance CXCR4 signaling and act synergistically with US27. In both HCMV-infected and US27-transfected cells, exposure to cmvIL-10 increased calcium and migration responses to CXCR4 ligand CXCL12. This cooperative effect may enable HCMV to manipulate CXCR4 to alter host immune responses and modify cell trafficking patterns. Overall, US27 has a wide range of functions that may alter activities of HCMV-infected cells.
Tu, Carolyn C., "The roles of human cytomegalovirus US27 gene product during virus infection" (2015). Master's Theses. 154.