Macrophage Biology and Disease Susceptibility in Poultry

Poultry are the largest source of animal protein world-wide. Sustainable production of meat and eggs requires the protection of the birds against a wide range of pathogens. Some of the current methods, including the use of antibiotics, are becoming less effective or have been banned because of hazards to human health. Our project combines two related approaches to overcoming some of the health issues of birds, by priming their immune systems either through the use of genetics or administration of natural proteins that normal control their immunity. Macrophages are large white blood cells that are first line of defence against pathogens, and also control the later acquired responses that are also induced by successful vaccines. Our project is based upon a number of proprietary discoveries about the way that macrophage biology is controlled in birds. On the one hand, we believe that there are many natural mutations in birds that compromise their immune systems and which have not been selected out in conventional breeding strategies. We aim to develop a simple assay that can detect the ability of macrophage to recognise and respond to a diverse set of infections, and show that the assay could be used to breed birds with improved disease resistance. On the other hand, we have identified a protein called CSF-1 which controls the numbers of macrophages in birds. We will test the ability of this protein to induce changes in growth and development of the immune system, and test the possibility that it could improve both innate disease resistance and the efficacy of existing and future vaccines.

This project is concerned with the genetic regulation of innate immune function in birds and the role of macrophage colony-stimulating factor (CSF1) and its receptor (CSF1R). The project is based upon previous successful projects, funded by BBSRC with several industry partners. These projects led to the cloning of avian CSF1 and IL34, the agonist of CSF1R, the generation of transgenic chicken lines in which control elements of Csf1r drive expression of reporter genes, and the production of a novel form of CSF1, CSF1-Fc, with a prolonged serum half-life and increased efficacy. The projects also builds upon extensive genomics sequence information derived from commercial birds.

This project investigates the development, regulation and function of macrophages in the chicken. The chicken is the most numerous farm animal in the world and chicken meat is predicted to soon become the most abundant meat (by weight) consumed. Although the chicken is therefore very important in terms of human food and food security, the research effort in understanding many important aspects of the chicken is relatively limited. One area that is of great importance, in relation to understanding response to diseases and to development of novel, effective vaccines, is the understanding of the basic biology of the innate and acquired immune system of poultry.
This will be of interest to the animal health companies (notably our major partner, Zoetis) that are involved in developing new, more effective vaccines for the major pathogens of commercial chickens. The protein to be tested in this project, CSF1, is covered by a wide-reaching patent, as is the generation of an active CSF1-Fc conjugate, which we will test for efficacy in a wide range of potential applications. Any new applications of CSF1 uncovered in this project have immediate pathways to translation.
We have also devised novel candidate vaccine vectors based upon our knowledge of the control of CSF1R transcription. Vaccination of chickens is increasingly carried out in the egg (before hatch) so improving our understanding of the development of the immune system in the post hatch period will be informative in development of vaccines. It is likely that the information generated on the transcriptome of mononuclear phagocytes will be valuable to annotation of the chicken genome and understanding the genetics of the innate immune response.
The poultry breeding industry, which has major bases in the UK, is increasingly using genomic information in breeding programmes to improve and speed up selection. We have multiple existing projects with several companies in the poultry breeding sector. Selection for improved robustness increases the economic value of commercial chickens and has health and welfare benefits. The project is based upon our existing data which indicates that there are significant genetic variation in genes that control macrophage function. We aim to devise an in vitro screen that would enable screening for resistance to numerous pathogen classes simultaneously and provide rapid feedback from the phenotypes of the progeny to enable assessment of breeding values in the progeny.