Atherosclerosis is the major cause of cardiovascular disease. It is recognized as an inflammatory disorder involving endothelial cell (EC) dysfunction and infiltration of macrophages and lymphocytes into the arterial wall, but the events contributing to the chronic inflammation remain elusive. Atherosclerosis preferentially develops in regions of the arterial tree with branches and curvatures where blood flow is disturbed and shear stress is low and non-uniform. There is increasing evidence that laminar blood flow with high shear stress modulates gene expression in ECs to protect against atherosclerosis and inflammation and that disturbed flow and low shear stress upregulates proatherosclerotic and proinflammatory genes. It has long been suspected that human cytomegalovirus (HCMV) infection is a risk factor for vascular disease such as atherosclerosis and restenosis following angioplasty. The key question is what is the mechanism underlying HCMV's role in the disease process? We hypothesize that infection of ECs and generation of a specific T cell response may be key factors. The significance of this proposal is that we will use a novel multifaceted approach to study interactions among HCMV, ECs, and PBMCs under conditions of flow and shear stress that closely mirror the conditions found in arteries susceptible to atherosclerosis. I brings together the extensive expertise in the Deborah Spector lab on molecular and cellular biology of HCMV and the broad experience in the Stephen Spector lab on HCMV pathogenesis, immunology, and translational medicine to test our hypothesis and assess the potential role of HCMV in atherosclerosis.
Two specific aims are proposed:
In Aim 1, we will determine how HCMV infection of aortic ECs impacts on expression of adhesion factors and inflammatory cytokines and chemokines under high vs. low shear stress.
In Aim 2, we will determine how HCMV infection of aortic ECs and differential adhesion of HCMV immunologically primed and naive PBMCs under different flow conditions contribute to EC dysfunction. The long-term objective of this proposal is to provide novel insights into the pathogenesis of atherosclerosis. Accomplishment of this goal will facilitate the development of new strategies designed to prevent and treat atherosclerotic disease.
Atherosclerosis is the major cause of cardiovascular diseases, and its impact on health care costs is huge. Hemodynamic factors are major regulators of atherosclerosis, and human cytomegalovirus (HCMV) infection has been put forward as an important factor in disease progression. The proposed project employs novel approaches to study the effect of HCMV infection on endothelial cell functions and the effect of the HCMV immunologic response on EC inflammation and damage under a dynamic flow environment.
|Clark, Alex E; Sabalza, Maite; Gordts, Philip L S M et al. (2018) Human Cytomegalovirus Replication Is Inhibited by the Autophagy-Inducing Compounds Trehalose and SMER28 through Distinctively Different Mechanisms. J Virol 92:|
|Belzile, Jean-Philippe; Sabalza, Maite; Craig, Megan et al. (2016) Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types. J Virol 90:1259-77|