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Just how do the poor chickens survive all those pathogens?

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At least 50 billion (that is, thousand million) chickens provide eggs and meat each year, the vast majority being commercial meat chickens originating from two global poultry breeding companies. Most chickens are densely-stocked under conditions which favour transmission of a huge range of pathogens. Vaccination is a major method for controlling disease but usually not transmission, leading to evolution of pathogens with changes in antigenicity, virulence and/or tropism. Another mode of protection is genetic resistance, for which there is much evidence in chickens, particularly for the major histocompatibility complex (MHC). MHC class I and class II molecules bind pieces of antigen (usually peptides derived from proteins, both self and non-self) and bring them to the surface of the cell where they can be recognised by T lymphocytes, a process termed “antigen presentation”. MHC molecules are generally highly polymorphic, with many alleles and much variation in sequence, mainly clustered around the peptide-binding groove. This variation (or “polymorphism”) is thought to be mainly driven by a molecular arms race with pathogens, which predicts that the MHC should strongly determine resistance and susceptibility to pathogens. There are many strong associations of the chicken MHC with infectious diseases, but the strong associations for the human MHC are with autoimmune diseases. Over the last 20 years, we have provided a molecular explanation for this functional difference, which is rooted in the evolutionary history of the MHC , particularly changes in genomic organisation that affect the interaction between proteins of the antigen presentation pathway. The result is that humans and most placental mammals express a multi-gene family of MHC molecules at high levels, so that each MHC haplotype confers more-or-less resistance to most pathogens, leading to weak genetic associations. In contrast, each chicken MHC haplotype expresses only one class I molecule (and one class II molecule) at a high level, and the properties of this “dominantly-expressed” MHC molecule in large part determines the immune response, leading to strong genetic associations. For a couple of viral infections and vaccinations, we have shown that the peptide-binding specificity of the particular MHC class I molecule can explain life or death of particular chickens. So, how do chickens survive all those pathogens, given that they have only a single dominantly-expressed MHC class I molecule? We have found that some haplotypes have class I molecules with peptide-binding specificities that are really “fastidious”, requiring particular amino acids as “anchor residues” in at least three places within an eight amino acid peptide. However, other haplotypes have peptide-binding specificities that are really “promiscuous”, binding an astonishing variety of peptides. These two kinds of haplotypes differ in a suite of properties, including cell surface expression level, peptide-transporter (“TAP”) specificity and resistance to the oncogenic herpesvirus that causes Marek’s disease. Our current hypothesis is that the promiscuous MHC molecules allow recognition by a much wider variety of T cells, resulting in a great and more effective immune response. Moreover, we find that haplotypes with promiscuous MHC molecules are extremely common among commercial meat chickens. Thus, it may be that commercial chickens survive their pathogens because they have MHC class I molecules that are generalists, much more like class II molecules than like human class I molecules.

This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.

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