The aim of this project is to define the molecular mechanisms by which blood leukocytes migrate to specific tissue sites that are inflamed or infected. We have focused on chemoattractant proteins that mediate this process and have identified members of a large family of chemoattractant receptors that are deployed on the leukocyte cell surface. We have also identified members of a diverse group of chemoattractant and chemoattractant receptor mimics made by viruses, including herpesviruses, poxviruses and HIV. We use genomics, molecular biology, cell biology and epidemiology as the principle methods for analyzing these molecules. A major goal is to identify specific disease associations of individual chemoattractant and chemoattractant receptors, in order to identify potential new therapeutic targets. To this end, in FY05 we developed a mouse model of West Nile Virus infection and discovered that the chemokine receptor and major HIV coreceptor CCR5 is critical for coordinating leukocyte trafficking to the brain, which facilitates viral clearance and mouse survival. This provides new insight into the pathogenesis of WNV, and raises a therapeutic concern about whether agents that block CCR5, which are now being developed for treatment of patients with HIV/AIDS, might induce increased susceptibility to severe WNV infection in these patients. We have also followed up our previous analysis of the inflammation hypothesis of atherosclerosis pathogenesis, and discovered that genetic variants of the chemokine MCP-1 gene are associated with increased circulating MCP-1 levels and myocardial infarction in the Framingham Heart Study. This strengthens the notion that chemokines are important in recruiting leukocytes to the vessel wall in this disease, and suggests MCP-1 as a potential therapeutic target. We have also continued to further understanding of the biology of the chemokine receptor CX3CR1 through our finding that its expression is oppositely regulated by the gamma-c cytokines IL-15 and IL-2 via selective NFAT1- and NFAT2-dependent mechanisms. This suggests that cell products expanded in response to IL-15 may be crippled in their ability to traffic to body sites rich in the CX3CR1 ligand CX3CL1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000615-15
Application #
7192922
Study Section
(LHD)
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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