The long-term goal of this project is to determine the role of viral pathogens in the development of vascular diseases such as atherosclerosis, restenosis, and transplant vascular sclerosis (TVS). All of these diseases are the result of either mechanical or immune related injury followed by inflammation and subsequent smooth muscle cell (SMC) proliferation and/or migration from the vessel media to the intima, which culminates in vessel narrowing. Clinical studies have directly associated human cytomegalovirus (HCMV) with the acceleration of TVS and restenosis as well as atherosclerosis. However, the mechanism(s) involved in the acceleration of vascular disease by HCMV is unknown. Studies by our group and others have implicated endothelial cells (EC), macrophages (MDM) and SMC as potential reservoirs of the virus in the host. Unfortunately, an animal model for HCMV is unavailable. However, mouse cytomegalovirus (MCMV) provides an ideal system to study mechanisms of pathogenesis and cellular tropism in the mouse model. Recently, we have developed a mouse heart transplantation model of TVS, which exhibits all of the hallmarks of human disease. We have also shown that CMV accelerates the progression and severity of TVS. Therefore, in this project we will utilize the mouse TVS model in combination with MCMV to assess the role of viral infection of MDM and EC on the acceleration of disease. In the first specific aim, we will utilize MCMV EC and MDM tropic mutants, which inhibit growth of virus in these cell types to assess the contribution of viral infection of these cells in the acceleration of TVS. In the second specific aim, we will utilize mice which specifically express Cre recombinase in EC and MDM in combination with recombinant MCMV that contain Lox sites which inactivate the virus in the presence of Cre enzyme to assess the role of MCMV replication in MDM and EC in the acceleration of TVS. In the last specific aim, we will examine viral mechanisms which accelerate TVS through ablation of MCMV genes which mediate inflammatory events.
Showing the most recent 10 out of 11 publications
