Epidemiological evidence suggests that cytomegalovirus (HCMV) infection is a major contributing risk factor to the development of accelerated graft arteriosclerosis (AGA) in heart transplant recipients. We have obtained evidence for non-lytic chronic or latent infection by in situ hybridization in up to 70% of coronary artery sections in CMV positive recipients exhibiting AGA. HCMV IE1 and IE2 RNA, but not the 2.7kb IR4 delayed-early RNA were found to be expressed in large numbers of infiltrating mononuclear lymphocytes or monocytes (MNC) and in many endothelial cells (EC) as well as in some clustered smooth muscle cells (SMC) in the intima. Patterns of HCMV IE1 and IE2 protein expression correlated with the RNA results but differed in each cell type with SMC predominantly expressing the IE1 protein; EC the IE2 protein and MNC synthesizing neither protein. No late proteins were detectable except in occasional mature macrophages in the myocardium with inclusion bodies. We hypothesize that the expression of a limited subset of viral transcriptional regulatory genes in these non-permissively infected cells may alter cellular gene expression and functional activity or the proliferation state of one or more of these cell types in ways that may trigger or exacerbate the changes involved in coronary arteriosclerosis.
The specific aims of this project are thus to 1) Definitively characterize the in situ status of viral regulatory gene expression in different cell types in vessel walls with and without disease. 2) Examine the effects of HCMV infection and IE1 or IE2 expression from adenovirus vectors on cellular levels of p53, TGF-beta and PDGF, in quiescent and non-permissive BC and SMC culture systems with a view towards understanding the mechanisms involved in relevant cellular changes. We will also focus on the mechanisms of CMV.induced over-expression of p53 and determine whether the absence of p53 genes affects AGA in the presence or absence of CMV in a transgenic knock-out mouse model. 3) Examine otherwise inaccessible early events (especially in proliferating SMC in the intima) in a latently infected donor rat model that produces AGA within 20 days after cardiac transplantation and utilize genetically marked rat CMV to follow reactivation events. Parts of the work will be carried out in collaboration with other groups in the project. Our anticipation is that detailed knowledge of the role of CMV and its close relatives HHV6 and HHV.7 in AGA will lead to a better understanding of how to manage and monitor the disease, as well as to the development of potentially useful therapeutic or preventative strategies.
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| Murata, Kazunori; Baldwin 3rd, William M (2009) Mechanisms of complement activation, C4d deposition, and their contribution to the pathogenesis of antibody-mediated rejection. Transplant Rev (Orlando) 23:139-50 |
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