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The modulation of sphingolipids by human cytomegalovirus and its influence on viral protein accumulation and growth

Machesky, Nicholas John
http://rave.ohiolink.edu/etdc/view?acc_num=osu1181753517

Abstract Details

2007, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science.
Human cytomegalovirus (HCMV) is a beta-herpes virus which can cause serious disease and even death in congenitally-infected infants and in immunocompromised individuals or immunosuppressed transplant recipients. Sphingolipids are structural components of cell membranes that can act as critical mediators of cell signaling. An unexplored area of research is whether HCMV modulates sphingolipids and their signaling pathways. Our data show that HCMV infection results in increased accumulation and activity of sphingosine kinase (SphK) within different cell types and occurs during early times of infection. Measuring the levels of transcripts encoding key enzymes of the sphingolipid metabolic pathway during HCMV infection revealed a temporal regulation of both synthetic and degradative enzymes of this pathway. Using mass spectrometry, we were able to generate a sphingolipidomic profile of HCMV-infected cells, which suggests an enhancement of de novo sphingolipid synthesis at early times of infection. This was followed by a decrease in the levels of several sphingolipids at 48 hrs, correlating with the upregulation of degradative enzymes. Then by knocking down SphK1 expression with siRNA, we showed that this enzyme may function within HCMV infected cells to sustain levels of the immediate early (IE) transactivator, IE1. Later, we show evidence suggesting that de novo sphingolipid biosynthesis is necessary for the production of optimal levels of infectious virus progeny, but has an intermediate product which suppresses the levels of IE1 protein accumulation. Through exogenous addition of dhSph, an intermediate of de novo sphingolipid synthesis, we show that this lipid can inhibit HCMV protein accumulation. dhS1P treatment, however, results in increased accumulation of HCMV proteins, although only at early times during infection. Moreover, pretreatment of cells with dhS1P or S1P prior to infection results in reduced accumulation of HCMV gene products, thus indicating a time-dependent need for increased dhS1P levels by HCMV. Finally, our results, using a drug inhibitor to suppress SphK activity during infection with HCMV, suggest that the stimulation of SphK activity may act to promote virus replication. These studies indicate that HCMV modulates sphingolipid metabolism to temporally regulate the levels of dhSph and dhS1P in order to optimize viral protein accumulation and growth.
James Van Brocklyn (Advisor)
120 p.
sphingolipids; cytomegalovirus; sphingosine kinase; S1P

Recommended Citations

Citations

  • Machesky, N. J. (2007). The modulation of sphingolipids by human cytomegalovirus and its influence on viral protein accumulation and growth [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1181753517

    APA Style (7th edition)

  • Machesky, Nicholas. The modulation of sphingolipids by human cytomegalovirus and its influence on viral protein accumulation and growth. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1181753517.

    MLA Style (8th edition)

  • Machesky, Nicholas. "The modulation of sphingolipids by human cytomegalovirus and its influence on viral protein accumulation and growth." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1181753517

    Chicago Manual of Style (17th edition)

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© 2007, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.