Discovery and characterization of cytomegalovirus entry factors

  • Tortorella, Domenico D. (PI)

Project Details

Description

Human cytomegalovirus (CMV) creates a latent reservoir in myeloid cells and the vascular endothelium. Viral reactivation from these sites maintains viral persistence and fuels dissemination. Populations at risk for CMV disease are immunocompromised individuals including newborns, transplant recipients, AIDS patients, and patients with cardiovascular diseases, autoimmune diseases, and cancer. Manifestations of CMV disease in these patient populations include neuronal defects in infants and gastrointestinal disorders, pneumonia, and end-organ disease in transplant recipients. Persistent CMV infection of the endothelium has also been linked to vascular inflammation and immune-mediated injury. CMV antigen, viral genome, and viral RNA have been detected in tissue from carotid arteries, aortic plaques, and atherosclerotic tissue in healthy and in patients with cardiovascular disease. Chronic infection of the vasculature with CMV has been linked to atherosclerosis, restenosis, and transplant vascular sclerosis. The infection of endothelial and monocytic cells is essential for the establishment of viral latency and allows for viral dissemination throughout the host. Despite the understanding of how CMV enters fibroblasts, there is a major knowledge gap in the molecular factors essential for CMV entry in these latency-associated cells. Thus, the objective of the current grant is to utilize functional-based high-throughput screens to discover and characterize cellular factors critical for CMV entry in endothelial and monocytic cells. We hypothesize that unique cellular proteins are critical for CMV infection in endothelial cells and monocytes. We plan to test our hypothesis utilizing a recently developed novel immunization strategy to generate monoclonal antibodies (mAbs) against diverse cell surface proteins using cell-derived membrane vesicles (CDMVs) as immunogen. The mAbs will be screened using a high-throughput neutralization assay followed by proteomic studies that will discover novel cellular factors critical for virus infection. The identified cellular factors may directly participate in virus infection as receptors or indirectly regulate cellular processes critical for a CMV infection and provide mechanistic insight into how virus enter these physiological important cell types. The mAbs targeting these proteins can also be developed into anti-CMV therapeutics as biologics to prevent the onset of CMV-associated diseases including cardiovascular disorders. (AHA Program: Grant-in-Aid)

StatusFinished
Effective start/end date1/07/1730/06/19

Funding

  • American Heart Association: $154,000.00

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