Award details

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

Reference	BB/P005659/1
Principal Investigator / Supervisor	Professor Kurt Drickamer
Co-Investigators / Co-Supervisors	Dr Maureen Taylor
Institution	Imperial College London
Department	Life Sciences
Funding type	Research
Value (£)	405,680
Status	Completed
Type	Research Grant
Start date	01/04/2017
End date	30/09/2020
Duration	42 months

Abstract

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.

Summary

The innate immune system is the first line of defence against invading pathogens. Cells of the innate immune system, such as macrophages and dendritic cells express a variety of receptors that bind to sugar (glycan) targets. These receptors, known as lectins, perform a dual function: under non-infectious conditions, they support the normal function of the immune system through enhancing the interaction of macrophages/dendritic cells with T cells. Under infectious conditions, they aide the recognition of pathogens that express specific glycan motifs in case of an infection. Distinguishing host cells from pathogens by these receptors derives from their ability to bind pathogen-specific surface sugars. Recently, the idea of using glycan structures as vaccine adjuvants/vaccine delivery systems to target specific innate immune cell subsets through the sugar-binding receptors has been explored. Using this approach robust humoral and cellular immune responses have been induced in mice. Thus, in addition to providing an understanding of innate immune cell - T cell interaction in farm animals in more detail, the proposed work will provide a basis for exploiting adjuvant-like properties of glycans themselves resulting from their ability to activate both inflammatory and phagocytic receptors expressed on antigen-presenting cells. Our preliminary data demonstrate that there are substantial differences between the glycan-receptors expressed in different mammalian species, and the ligands that they recognise. This observation has important implications for vaccine design for farm animals, specifically ruminants as studied here, as it means that vaccine adjuvants designed and tested in the human and/or murine system may not work in other mammalian species, a fact supported by the recent failure of mycobacterial vaccines in the appropriate host. Thus, identifying the glycan (lectin) receptors in the bovine genome and understanding their function may provide new avenues to understand the first steps in host pathogen interaction. As the key way of reducing antibiotic dependence, and thus the reduction of AMR is to improve current vaccine strategies, the gained knowledge may also provide the basis for the development of more host-specific adjuvant/vaccine-delivery systems.

Impact Summary

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.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Animal Health, Immunology, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/P008461/1 Creating a bovine C-type lectin receptor atlas and identification of their ligands

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