REAL-TIME ANALYSES OF MAIT CELLS' RESPONSES TO INFECTION

Our immune system is composed by many different immune cells that function together in a coordinated fashion to protect us from disease. Immune cells are very dynamic and constantly patrol the body on the look-out for infectious virus and bacteria. Consequently, the correct location of immune cells in the body (being in the right place at the right time) is extremely important for them to be able to efficiently find and destroy invading pathogens. While for many years immune responses to pathogens could only be studied in vitro (outside the body), the recent development of novel microscopy techniques enables scientists to directly visualize -within the body and in real time- immune cells combating pathogens. Our research aims to take advantage of these novel techniques to provide unique insight into the processes that initiate immune responses to bacterial infections. We focus on a specific population of immune cells- so called MAIT cells- which are known to be important in fighting bacterial infections. However how, where and when MAIT cells find and destroy bacteria in vivo remain unknown. In this proposal we intend to provide this understanding, by using our combined expertise in microscopy, immunology and microbiology to reveal the molecules and processes by which MAIT cells fight bacterial infections and how in turn bacteria subvert the immune system to survive in the host. The findings of this proposal may serve as the foundation for novel therapeutic and prevention strategies to treat infectious diseases

Immune cells are highly dynamic and constantly patrol the tissues and interact with each other to maintain homeostasis and respond to invading pathogens. The correct anatomical location of immune cells is critical to modulate their activation and function and will ultimately control the outcome of immunity. Populations of tissue-resident innate immune cells function as sentinels for infection and are strategically situated in the tissues ready for rapid response to infectious challenges. Within the families of innate lymphocytes mucosal-associated invariant T (MAIT) cells have recently emerged as key players against bacterial infections, as they specifically recognize bacterial-derived riboflavin metabolites. However little is known about the complex interplay between MAIT cells and bacteria in vivo. In this proposal we intend to provide this understanding, by uncovering fundamental aspects of MAIT cell organization and behaviour that underpin the initiation of protective immunity against bacterial infections. Using our newly developed transgenic models in combination with intravital microscopy, we will provide first-ever data regarding the spatiotemporal organization of MAIT cells in living tissues. With this established, we will focus on the response of these cells to infection, using Klebsiella -a riboflavin-producing antibiotic-resistant bacterium- as a model pathogen. By combining immunology, microbiology and imaging techniques we will define in real-time the anatomical foci and cellular crosstalk controlling MAIT cell activation during Klebsiella infection, will shed light on pathogen spread through the tissues and will identify the mechanisms by which MAIT cells contribute to bacterial clearance. In a context of growing antibiotic resistance, our research will provide a great leap forward in our understanding of host-pathogen interactions and offer rationale for the design of new therapies to treat infectious diseases.

The impact from this research can be integrated in 3 main areas:

Contribution towards science, generation of knowledge and worldwide academic advance: The short-term beneficiaries from this research will be scientists working in a broad range of disciplines. This state-of-the-art project represents a significant step forward on our understanding of the mechanisms regulating immunity to bacterial infection. We anticipate that our results will shed light on general principles of bacterial immunity and will be therefore of great interest to the Immunology, Infection and Microbiology communities. Moreover, the use and development of new genetic models and in vivo imaging techniques will be of interest for scientists working in a variety of disciplines and open the door to new collaborative projects. The main collaborative interactions will be with Prof Bengoechea (Queen's University Belfast) on Klebsiella infection biology and Prof Klennerman (University of Oxford) in MAIT cell biology. However, we anticipate exciting new collaborations with groups focusing on immune cell imaging, infection models and with clinicians working on prevention and treatment of hospital-acquired infections and antimicrobial resistance. 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: Staff working on the project will receive training on a variety of skills (communication, public engagement) which together with cutting-edge research training will provide them with a full range of options for a successful career in academia or industry. The trainees will be involved in general dissemination strategies (conferences, publications, public engagement). Also, our lab will host summer BSc students and A-Level science students to give them the opportunity to learn first-hand about science and inspire them to pursue a scientific career.

Public health and welfare: The rapid spread of multi-resistant bacteria and the lack of new antibiotics to treat infections caused by these organisms poses a rapidly increasing threat to public and animal health. Thus, the development of novel therapies for emerging antibiotic-resistant bacteria such as Klebsiella is of the highest priority both for the UK and international research communities. This proposal aligns with the "5-year antimicrobial resistance strategy" set by the UK government and aiming to stimulate national and international action to tackle this global issue. Although our research will focus on Klebsiella, we anticipate that our results will shed light on general principles of bacterial immunity and could therefore identify new therapeutic targets for the treatment of a broad range of infectious agents. 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.
To facilitate communication of the research to the general public and policy makers, both the Francis Crick Institute and KCL count with a Press Office to manage relations with media and facilitate public broadcast of scientific breakthroughs. Work will be published and publicised by several means such as press releases to national and international media, press conferences, web stories, podcasts, videos and/or panel discussions/debates held for the media and general public. Interactions with KCL clinicians (Centre for Clinical Infection and Diagnosis Research, St Thomas' Hospital, KCL) and industry will facilitate translation to clinics in the form of clinical trials and new academic-industry partnerships.