Molecular Studies of Host-pathogen Interactions in Human Cytomegalovirus-infected Myeloid Cells
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University of Cincinnati / OhioLINK
2015
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ndltd-OhioLink-oai-etd.ohiolink.edu-ucin14393086832021-08-03T06:32:47Z Molecular Studies of Host-pathogen Interactions in Human Cytomegalovirus-infected Myeloid Cells Wu, Shu-en Virology human cytomegalovirus vitamin D US28 myeloid cells YM-254890 G protein-coupled receptor Human cytomegalovirus (HCMV) is a member of the subfamily of Beta-herpesviridae that establishes latency in human hematopoietic progenitor cells, myeloid progenitor cells and monocytes. While the serological positive population is prevalent worldwide, this virus does not cause severe symptoms in immunocompetent individuals. However, in immunocompromised patients and developing fetuses, this virus can cause serious morbidity and mortality. In light of many chronic diseases in the modern world leading to immunodeficiency and organ transplants, the importance of HCMV in medical research and public health is rising. Although it is known that HCMV establishes latency after primary infection, the molecular mechanism(s) that controls latent/lytic switch remains elusive. In addition, there is limited knowledge about stimuli that could induce the myeloid cells to support HCMV lytic phase. In this thesis, we studied the effect of vitamin D, a hormone produced by human body or acquired from diet, on HCMV replication in peripheral monocytes and THP-1 cells. We found that vitamin D induces monocyte differentiation to facilitate HCMV replication, and instead of causing a direct up-regulation of HCMV immediate-early gene promoter (MIEP) activity as phorbol 12-myristate 13-acetate (PMA) treatment, the vitamin D induced monocyte differentiation causes an open chromatin structure around MIEP enhancer region of HCMV genome which also happens in PMA treated monocytes.In Chapter III of the thesis, we examined the Gαq dependent signaling pathways triggered by herpesviruses encoded G protein-coupled receptors by using Gαq specific inhibitor (YM-254890). We found that the inositol triphosphate accumulation triggered by US28 and M33 can be blocked by the inhibitor but the inositol triphosphate accumulation initiated by ORF74 cannot be suppressed by the inhibitor. In addition, CREB and NFAT activated by US28 and M33 can also be inhibited by the inhibitor, showing that they are Gαq dependent. However, for both US28 and M33, NF-κB is Gαq independent. Although ORF74 activates the same downstream signaling molecules including CREB, NFAT, and NF-κB, none of these is activated by Gαq dependent signal. Finally, in Chapter IV of this thesis, we study the expression and function of US28 in THP-1 cells and monocytes. Our data showed that US28 protein is expressed in infected THP-1 cells, and that ectopic expression of US28 kindles Gaq dependent inositol triphosphate accumulation in THP-1 cells. In addition, the US28 triggered constitutive Gaq signal negatively regulates random migration and chemotaxis, and promotes THP-1 cells to adhere to endothelial cells though Gαq-PLCß-PKC signal axis. 2015-09-11 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439308683 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439308683 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Virology human cytomegalovirus vitamin D US28 myeloid cells YM-254890 G protein-coupled receptor |
| spellingShingle |
Virology human cytomegalovirus vitamin D US28 myeloid cells YM-254890 G protein-coupled receptor Wu, Shu-en Molecular Studies of Host-pathogen Interactions in Human Cytomegalovirus-infected Myeloid Cells |
| author |
Wu, Shu-en |
| author_facet |
Wu, Shu-en |
| author_sort |
Wu, Shu-en |
| title |
Molecular Studies of Host-pathogen Interactions in Human Cytomegalovirus-infected Myeloid Cells |
| title_short |
Molecular Studies of Host-pathogen Interactions in Human Cytomegalovirus-infected Myeloid Cells |
| title_full |
Molecular Studies of Host-pathogen Interactions in Human Cytomegalovirus-infected Myeloid Cells |
| title_fullStr |
Molecular Studies of Host-pathogen Interactions in Human Cytomegalovirus-infected Myeloid Cells |
| title_full_unstemmed |
Molecular Studies of Host-pathogen Interactions in Human Cytomegalovirus-infected Myeloid Cells |
| title_sort |
molecular studies of host-pathogen interactions in human cytomegalovirus-infected myeloid cells |
| publisher |
University of Cincinnati / OhioLINK |
| publishDate |
2015 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439308683 |
| work_keys_str_mv |
AT wushuen molecularstudiesofhostpathogeninteractionsinhumancytomegalovirusinfectedmyeloidcells |
| _version_ |
1719438893613318144 |