Epstein Barr virus (EBV) is a cause of infectious mononucleosis and is associated with a number of cancers including Burkitt lymphoma and lymphoma in transplant recipients. Chronic active EBV (CAEBV) disease is an often fatal disease in which patients have markedly elevated levels of antibody to EBV or EBV DNA in the blood, and infiltration of tissues with EBV-infected lymphoocytes. In collaboration with Michael Lenardo in the Laboratory of Immunology, we found that one of our patients with CAEBV disease who died of an EBV-positive lymphoma had a mutation in a gene important for magnesium transport (MagT1). Another patient who had an inability to control EBV infection was also found to have a mutation in MagT1. These patient's T cells had reduced baseline levels of free magnesium and defective magnesium and calcium influx when they were treated with a potent T cell stimulus (antibody to the T cell receptor). The patient's peripheral blood cells were impaired for activating several proteins in signaling pathways (NF-KB, NFAT, PLC-gamma 1, PKC-theta), Since T lymphocytes are important for killing EBV-infected cells, impaired activation of T lymphocytes in the patient due to the mutation in MagT1 was likely responsible for his severe CAEBV disease. We have been studying other cellular genes that are important for controlling EBV infection. We collaborated with Joshua Milner in the Laboratory of Allergic Diseases and found that patients with mutations in a gene important for signaling T lymphocytes, STAT-3, have an impaired ability to control EBV and varicella-zoster virus infection. These patients have elevated levels of EBV DNA in the blood compared with controls and lower levels of memory T cells that react with EBV. The patients also have higher rates of zoster and episodes of zoster which occur much earlier in life than healthy persons. They also have a reduced number of memory T cells that can respond to varicella-zoster virus.

Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2012
Total Cost
$560,848
Indirect Cost
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State
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