CD1d AS A NOVEL REGULATOR OF INNATE IMMUNITY

Toll-like receptors (TLR) are a group of proteins that play a key role in the immune system by functioning as a first barrier for the recognition of pathogens such as virus or bacteria. The recognition of such pathogens by TLRs initiates a cascade of activation of immune cells that ultimately leads to pathogen elimination. However, the inappropriate activation of TLRs can be detrimental for health as in the case of autoimmune diseases or sepsis. Thus, understanding the processes that control the activation of TLRs is critical to modulate the balance between protective and pathogenic immune responses. Recent studies have proposed a role for the lipid cholesterol as a key regulator of TLR signalling. This suggests that controlling the cholesterol synthesis pathways (for instance by using statins) could be a tool to potentiate or dampen immune responses. However, the detailed processes regulating the crosstalk between immune cell activation and cholesterol metabolism remain unclear. The main aim of this proposal is to understand the pathways that link cholesterol metabolism and TLR responses. We will study in-depth the pathways that control TLR activation, investigate how they relate to cholesterol metabolism and evaluate their function during bacterial infection. Understanding the mechanisms regulating TLR activation will help design better strategies for prevention and treatment of infectious and inflammatory diseases.

Toll like receptors (TLR) are vital components of the innate immune system which bind pathogen-associated molecular patterns and control the secretion of cytokines which are crucial for pathogen clearance. Conversely, inappropriate TLR activation can be harmful in many conditions such as autoimmune diseases or sepsis. Therefore, the strict control of the pathways leading to TLR activation is critical for the regulation of immunity. A key mechanism involved in the regulation of TLR signalling relays on the complex interplay between innate immune responses and cholesterol metabolism. Indeed, perturbations in the cholesterol synthesis pathway regulate the secretion of cytokines by macrophages in homeostasis and in response to TLR stimulation. Consequently, manipulating cellular metabolism could beneficially enhance or curb immune responses. However, our understanding of this metabolic-inflammatory circuit is still very limited and the molecular pathways controlling this crosstalk and how it regulates macrophage function remain poorly explored. Unpublished data from our lab has identified an unexpected role for the antigen-presenting molecule CD1d in the control of TLR responses and its link to the cholesterol synthesis pathway. In this proposal, we aim to use our combined expertise in Immunology, Metabolism and Infection to identify the molecular mechanisms by which CD1d controls innate immune activation and to provide mechanistic understanding of the processes linking cholesterol metabolism and immunity in health and disease. We anticipate that our results will shed light on general principles of immunity and metabolism and could identify new therapeutic targets for a broad range of inflammatory and infectious diseases where a metabolism-immunity axis is beginning to emerge.

The impact from this research can be integrated in three main areas:
Contribution towards science, generation of knowledge and worldwide academic advance: The short-term beneficiaries of this project will be the scientific community. This state-of-the-art project represents a significant step forward on our understanding of the mechanisms regulating innate immunity and the link between immune responses and metabolism. We anticipate that our results will shed light on general principles of innate immunity and will be therefore of great interest to those working in Immunology and Infection. Also, we will provide evidence of the increasingly recognised importance of the metabolic regulation of immunity which will be of interest to scientists working in metabolism in a variety of contexts or those working in disease models where a dysregulation of cholesterol metabolism has been reported (i.e. rheumatoid arthritis, atherosclerosis). The main collaborative interactions will be with Prof Ghazal (Cardiff University) on metabolism and Dr O'Garra (Francis Crick Institute) on bacterial infections. However, we anticipate exciting new collaborations with groups focusing on metabolism, infection models and with clinicians working on prevention and treatment of infectious, metabolic and inflammatory diseases. The results arising from this proposal will be made accessible to academics by publishing them in peer-reviewed journals and presenting them in national and international meetings.
Training of highly skilled researchers: The proposed project will provide the staff member working on the project with training in a variety of scientific, conceptual and transferable skills which will broaden their future career perspectives in academia or industry. This will include: training in molecular and cellular Immunology, metabolism biology and infectious diseases; technical skills (flow-cytometry, in vivo experiments, lipidomics); transferable skills (communication skills, presentation and public speaking, independent thinking). The trainees will be involved in general dissemination strategies (conferences, publications, public engagement).
Public health and welfare: A focal point of this project is to decipher the mechanisms controlling bacterial infection in vivo using Listeria monocytogenes as a model pathogen. Listeria is primarily transmitted by ingestion of contaminated food and constitutes a major burden for the food industry as it can cause serious diseases in both humans and farmed animals. Listeria can grow in a variety of harsh conditions and multidrug-resistant Listeria isolates have been recently identified, making them difficult to treat and resulting in a 15-20% mortality rate. Thus, understanding the mechanisms controlling Listeria spread is of critical priority in order to develop new approaches to prevent and treat infections in humans and farmed animals. Although our research will focus on Listeria, we anticipate that our results will shed light on general principles of immunity and metabolism and could therefore identify new therapeutic targets for the treatment of a broad range of inflammatory and infectious diseases where a metabolism-immunity axis is beginning to emerge (including rheumatoid arthritis, sepsis or viral infections). These potential new therapies will benefit the general public and UK health system with medium-to-long term impact on clinical practise and new academic-industrial partnerships