Pattern recognition receptors and the recruitment and differentiation of myeloid cells in inflammation.
Lead Research Organisation:
CARDIFF UNIVERSITY
Department Name: School of Medicine
Abstract
The main aims of the research are to understand how the immune receptor dectin-1 controls the inflammatory response after fungal infection and to develop new experimental mouse models to facilitate these and related studies of inflammation.
At the time of an infection, the body initiates an inflammatory response, the aim of which is to recruit specialised immune cells to the site of infection and contain the infectious organism. The cells express receptors on their surface that are able to recognise distinct components of microorganisms. The collective recognition of multiple microbial components by many cell surface receptors enables the immune cells to ‘identify‘ the infecting organism and promote the development of an appropriate immune response.
Dectin-1 is a key receptor involved in the recognition of fungi that binds to fungal specific carbohydrates (beta-glucans). We have shown that this receptor is essential for a normal inflammatory response after fungal infection of mice and that its absence results in increased susceptibility to infection.
Fungal infections are important because of their increasing frequency as a consequence of modern medicine and acquired defects in the immune system. These studies will help us understand how a normal protective immune response to fungal infection occurs.
At the time of an infection, the body initiates an inflammatory response, the aim of which is to recruit specialised immune cells to the site of infection and contain the infectious organism. The cells express receptors on their surface that are able to recognise distinct components of microorganisms. The collective recognition of multiple microbial components by many cell surface receptors enables the immune cells to ‘identify‘ the infecting organism and promote the development of an appropriate immune response.
Dectin-1 is a key receptor involved in the recognition of fungi that binds to fungal specific carbohydrates (beta-glucans). We have shown that this receptor is essential for a normal inflammatory response after fungal infection of mice and that its absence results in increased susceptibility to infection.
Fungal infections are important because of their increasing frequency as a consequence of modern medicine and acquired defects in the immune system. These studies will help us understand how a normal protective immune response to fungal infection occurs.
Technical Summary
The primary aims of this research are: i) to determine the importance of the leukocyte beta-glucan receptor, Dectin-1, in the regulation of myeloid cell recruitment, activation, differentiation and survival during fungal infection; and ii) to develop novel models for the study of myeloid cells during inflammation.
Our initial characterisation of the leukocyte ?-glucan receptor, Dectin-1, has shown that it is broadly expressed on myeloid cells and plays a fundamental and non-redundant role in the recognition and response to fungi. Deficiency in Dectin-1 results in susceptibility to Candida albicans infection and this is associated with defective inflammatory responses. The increasing prevalence of fungal infections associated with acquired immunodeficiency and medically induced immunosuppression and the importance of Dectin-1 in anti-fungal defence have highlighted Dectin-1 as a potential therapeutic target.
It is important to understand how Dectin-1 regulates the anti-fungal inflammatory response to appreciate novel ways of manipulating the cellular response during inflammation. To achieve the aims of this proposal we will also develop models for the study of myeloid cell biology during inflammatory responses. These models will be important, not only for the study of the role of Dectin-1 in inflammation but also as a basis for improving the study of myeloid cells in models of human disease.
Our initial characterisation of the leukocyte ?-glucan receptor, Dectin-1, has shown that it is broadly expressed on myeloid cells and plays a fundamental and non-redundant role in the recognition and response to fungi. Deficiency in Dectin-1 results in susceptibility to Candida albicans infection and this is associated with defective inflammatory responses. The increasing prevalence of fungal infections associated with acquired immunodeficiency and medically induced immunosuppression and the importance of Dectin-1 in anti-fungal defence have highlighted Dectin-1 as a potential therapeutic target.
It is important to understand how Dectin-1 regulates the anti-fungal inflammatory response to appreciate novel ways of manipulating the cellular response during inflammation. To achieve the aims of this proposal we will also develop models for the study of myeloid cell biology during inflammatory responses. These models will be important, not only for the study of the role of Dectin-1 in inflammation but also as a basis for improving the study of myeloid cells in models of human disease.
