Creating a bovine C-type lectin receptor atlas and identification of their ligands

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

In the work proposed here, we will identify genes encoding C-type lectin receptors (CLRs) within the bovine genome and characterise the ligand-binding spectrum of selected CLRs. This knowledge will be subsequently used to investigate the functions of the selected CLRs in normal immune system homoeostasis as well as to assess their roles in binding and uptake of specific (and sometimes zoonotic) pathogens. We will build on preliminary studies performed in the laboratories of the two Principal Investigators to validate differences in ligand-binding of bovine CLRs compared to their human/murine counterparts, and to assess the immune response of antigen-presenting cell subsets to antigens delivered by CLR ligands. The test systems developed within this proposal will use state-of-the art lectin arrays to identify the ligand-binding spectrum of bovine CLRs. Given the existing knowledge of human CRL binding to specific pathogens, we will subsequently assess the importance of identified CLRs in the binding/uptake of Mycobacterium bovis, Listeria monocytogenes and bovine viral diarrhoea virus. All of these diseases are endemic in UK livestock and pose major animal/public health concerns with significant impacts on food security, food safety and economic productivity. We will investigate which pathogens are recognised and which glycans mediate the recognition by bovine CLRs, to identify new intervention strategies. Major outputs will include an on-line atlas of CLRs encoded in the bovine genome including, where possible, annotation of their specific chromosomal locations; documentation of the ligand-binding spectrum of these CLRs using glycan arrays; and demonstration of the functions of the CLRs in normal antigen-presenting cell - T cell interactions. A further key outcome will be an assessment of the importance of specific CLRs in the binding and uptake of (zoonotic) pathogens, with the ultimate aim of bridging the gap between tool development and practical use.

Infectious disease is a major problem in the farm industry world-wide and is one of the most important issues facing animal welfare. One of the most effective ways to combat current and emerging diseases is to maximise an animal's immune response, with the innate response, and the early activation of the adaptive response, being seen as increasingly important in this process. The appropriate activation of single, or groups of, Pattern Recognition Receptors (PRR) has been proposed to be a fundamental step in the induction of the immune response to challenge. We aim to isolate and characterise PRRs, specifically C-type lectin receptors (CLR) in ruminants, to identify genetic variation likely to have a large effect on response to infection and therefore disease susceptibility, and to investigate their responses to specific pathogens. In this way, we can directly test the role of CLRs in genetic resistance to common ruminant pathogens and provide markers that may be used as selection criteria by the farm industry. Information obtained about CLR function can also be used to design strategies for modifying or enhancing CLR signalling thereby altering the course of specific bacterial, parasitic or viral infections. In particular, a greater understanding of the role of CLR-mediated phagocytosis and signals in directing the immune response would also have considerable impact in the design of new adjuvants and novel vaccine strategies for the control of ruminant disease.
This research contributes to science objectives 1, 3 and 6 of the BBSRC strategic plan and falls within the remit of the Animal Sciences committee under both priorities of the theme "Mechanisms of immune function and disease pathogenesis". It will provide fundamental information on how the ruminant immune system functions and underpin long term commercial aims for improved therapeutic and preventative methods to reduce infectious disease in cattle. Through establishing whether CLR are part of the ruminant microbial recognition system and comparing the function of these molecules in rodents, human and ruminants, this project will also fall under the priority of functional and comparative genomics.

Welfare impact - benefits to cattle
The expectation today is that all farm livestock should have "a life worth living - from their point of view" (Farm Animal Welfare Council, 2009). Welfare would benefit if health status was improved. This proposal may provide the basis for development of carbohydrate-based vaccines in ruminants and, if successful, encourage farmers to potentially change their approach in treating specific infectious diseases, reducing their reliance on antimicrobial drug therapy.