The aim of this project is to define the molecular mechanisms and biological contexts for blood leukocyte migration 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. A key strategy is to analyze phenotypes of gene knockout mice in disease models as well as associations of loss of function mutations in the corresponding human genes in human disease cohorts. In FY08 we reported discoveries in the following three diseases: 1. West Nile virus pathogenesis; 2. skin wound healing; and 3.) epidermodysplasia verruciformis. ? 1.) We found that patients from Illinois and California infected with West Nile virus who lack the chemokine receptor CCR5, due to homozygous mutation CCR5D32, are at increased risk of developing symptomatic disease. This work confirms a similar analysis reported by our group in 2006 in infected individuals from Arizona and Colorado. Moreover, it is consistent with results we reported in 2005 using a model of WNV infection in mice lacking CCR5. The recent work is important because candidate gene association studies with infectious disease phenotypes must be replicated to establish credibility. The WNV work is particularly difficult because this is an ongoing emerging epidemic; moreover, the work is difficult because it is difficult to obtain useful samples. The overall results are scientifically important because they identify the first genetic risk factor for WNV disease and the first beneficial role in humans for CCR5. The significance extends beyond WNV to HIV/AIDS since CCR5 is exploited by HIV to enter target cells and since CCR5 antagonists are now being used in patients with HIV/AIDS. The new data suggest that blocking CCR5 with a drug may increase the risk of symptomatic WNV disease should treated patients become infected with WNV. ? 2.) In FY08 we reported new results identifying the chemokine receptor CX3CR1 as an important factor in a skin wound healing model in mice. The receptor appears to work by coordinating macrophage accumulation in wounds, which are important for orchestrating clearance of debris, new blood vessel formation, and fibrosis. This work is important because it identifies CX3CR1 as a candidate regulatory factor in human wound healing. Identifying such factors may help guide development of novel treatments to accelerate wound healing and reduce the risk of infection.? 3.) In FY08 we also reported two cases of the disease epidermodysplasia verruciformis lacking known mutations in two genes previously shown to be associated with this disease, EVER1 and EVER2. The results will stimulate a search for the causal mutations in these patients. The broader issue though is to identify genetic factors that control susceptibility to infection wtih human papillomavirus, which causes the warts in epidermodysplasia verruciformis and other diseases. We identified these patients and performed this work in the context of our interest in the molecular immunopathogenesis of WHIM syndrome, a rare immunodeficiency characterized by warts, hypogammaglobulinemia and myelokathexis (neutropenia due to retention of neutrophils in the bone marrow) and caused by truncating mutations in the C-tail of the chemokine receptor CXCR4. Our EV patients did not have abnormalities in CXCR4. Understanding how HPV takes advantage of genetic deficiencies in severe cases of warts may lead to new ideas for treating not only these patients, but the much larger general population which frequently suffers from common warts.
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