Faraday earmarked proposal: Toll-like receptors and dendritic cell genetic heterogeneity

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Improvement in the efficacy of vaccines and the identification of genetic traits affecting disease resistance will have a large impact on disease control in livestock. Many current vaccines are live vaccines with limited long term protection. Variable responsiveness to vaccines has been observed across populations and includes non-responsiveness as well as pathogenic responses. Disease resistance traits are also highly variable both between and within breeds. Variability in both vaccine responsiveness and disease resistance traits can have moderate to high heritability and the genes underlying these traits are likely to overlap, and involve both Major Histocompatibility Complex (MHC) and non-MHC genes. Major goals for the UK pharmaceutical and breeding industries would be to create uniformly efficacious non-live subunit vaccines for livestock and identify suitable markers for breeding for disease resistance and vaccine responsiveness. Our contention is that there will be genes underlying these traits that are expressed in the innate immune system. Specifically, this proposal will concentrate on the expression, function and polymorphism of pathogen- recognition receptors (PRR), specifically the toll-like receptors (TLR) found on authentic dendritic cells (DC) derived from cattle and sheep afferent lymph. These cells are a major component of the innate immune system and form an instructive link between the innate and acquired (adaptive, antigen-specific lymphocyte-mediated) immune systems.