Cytomegalovirus Pathogenesis in Immunodeficiency

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DESCRIPTION (provided by applicant): Human cytomegalovirus (CMV) remains the most important infectious cause of sensorineural hearing loss as well as a significant cause of acute and chronic disease in solid organ and hematopoietic cell transplant recipients. CMV pathogenesis relies on leukocyte-associated viremia to disseminate virus within the host. All CMVs encode potent chemokines and murine CMV chemokine MCK-2 exploits the host inflammatory response, mobilizing bone marrow leukocyte progenitors to initial sites of infection that become vehicles to enhanced dissemination via the bloodstream to specific sites in the infected host. Less is known about the role of human CMV vCXCL-1 chemokine in pathogenesis or latency. This project seeks to define the initial events during human and murine CMV infection to understand how viral exploitation of the host inflammatory response contributes to dissemination and latency. Properties of murine CMV MCK-2 will be studied in mouse cells and the mouse host in order to characterize the mechanism of recruitment of myeloid progenitors from bone marrow and the pathway that the virus follows to disseminate within the host. Properties of human CMV vCXCL-1 will be studied in mice reconstituted with functioning human hematopoietic cells to identify the myeloid cell type that is recruited by this chemokine and that may be intermediaries in dissemination. The First Aim will identify the phenotype of cells that respond to MCK-2, identify the MCK-2 receptor, investigate the myeloid type that disseminates virus via the peripheral blood and identify host chemokine and cytokine components that contribute to the MCK-2 response. This aim will also investigate comparatively the biological impact of vCXCL-1 on human cells in culture and in mice to identify responding myeloid cell types that may be implicated in human CMV dissemination. The Second Aim will track the murine CMV dissemination pathway to determine whether myeloid cells become infected directly in tissues or acquire virus from vascular endothelial cells as intermediate host cells leading to viremia. The Third Aim will investigate viral and cellular gene expression profiles in infected cells and tissues, employing viruses that encode a uracil phosphoribosyl transferase enzyme to allow specific enrichment of mRNA from infected cells within populations of uninfected cells, such as occurs in tissues. These studies will provide important new comparative insights on human and murine CMV pathogenesis and latency.