Organ System/Disease Focus:
Aligned Research Focus:
Human cytomegalovirus (HCMV) is a significant human pathogen that remains associated with the infected host for the life of the individual because it can establish a latent infection. During latency, HCMV avoids immune detection and clearance while retaining the ability to reactivate at a later point to produce infectious progeny virions (lytic replication) and disease. The natural reservoir of latent HCMV infections is thought to be an undifferentiated cell of the myeloid lineage, and it is often studied in vitro in CD34+ hematopoietic stem cells. However, CD34+ cells are difficult to maintain in an undifferentiated state, and thus a long-term latency model for HCMV does not exist. Because embryonic stem (ES) cells can be maintained in an undifferentiated state, we plan to explore if ES cells will support HCMV latency and reactivation. Furthermore, we plan to examine if complete or partial reprogramming of fibroblasts into induced pluripotent stem (IPS) cells can also be used to study the mechanisms required for the establishment, maintenance, and reactivation of HCMV latency.
We also plan to initiate a project examining potential roles of HCMV infection in cancer stem cells associated with gliobltastoma multiforme (GBM) tumors. Recently, we identified HCMV sequences in GBM tumor samples. Interestingly, our analysis indicated that only a small portion of the cells within these tumor samples were actually infected with HCMV. We plan to determine if tumor stem cells found in GBMs are preferentially infected with HCMV. Cancer stem cells are receiving increased scrutiny for their roles in perpetuating tumors. Were HCMV to preferentially infect glioma stem cells, it may mean that the virus has an oncogenic role in these tumors, and that antiviral therapies could potentially have anti-tumor effects.
- Lee SH, Albright ER, Lee JH, Jacobs D, Kalejta RF. Cellular defense against latent colonization foiled by human cytomegalovirus UL138 protein. Sci Adv. 2015 Nov 27;1(10):e1501164. doi: 10.1126/sciadv.1501164. eCollection 2015 Nov. PMID: 26702450
- Penkert R.R., Kalejta, R.F.. Human Embryonic Stem Cell Lines Model Experimental Human Cytomegalovirus Latency. MBio. 2013 May 28;4(3):e00298-13. doi: 10.1128/mBio.00298-13.
- Ranganathan, P., Clark, P.A., Kuo, J.S., Salamat, M.S., and Kalejta, R.F. (2012) Significant association of multiple human cytomegalovirus genomic loci with glionblastoma multiforme samples. J. Virol. 86, 854-864. PMCID: PMC3255835
- Saffert, R.T., Penkert, R.R., and Kalejta, R.F. (2010) Cellular and viral control over the initial events of human cytomegalovirus experimental latency in CD34+ cell. J. Virol. 84 (11) 5594-5604.
- Hume, A. J., Finkel, J. S., Kamil, J. P., Coen, D. M., Culbertson, M. R., and Kalejta, R. F. Phosphorylation of Retinoblastoma Protein by Viral Protein with Cyclin-Dependent Kinase Function. Science, 320: 797-799, 2008.