Characterisation of the C-type lectin receptor CLECSF8 (CLEC4D)
Lead Research Organisation:
University of Aberdeen
Department Name: Division of Applied Medicine
Abstract
Despite over a century of research, Mycobacterium tuberculosis remains one of the deadliest bacterial infections, resulting in over one and a half million deaths each year. Priorities to combat this global problem are the development of new antitubercular drugs and a more effective vaccine; both of which depend, in large part, on obtaining a better understanding of interactions between the host and this bacterial pathogen. We have identified a novel molecule (receptor) found on the surface of immune cells which appears to be involved in the control of M. tuberculosis during infection. Elucidating the functions of this receptor will provide substantial new insights into how the host combats these infections. To do this, we will make use of mouse models of infection by comparing normal mice to mice which lack this receptor. We will look at a variety of responses that may be influenced by the receptor, including how the host responds immediately upon infection (innate response) as well as responses later during infection, once the host has had time to recognise and respond specifically to M. tuberculosis (adaptive response). We will also look at the responses of individual cells to better understand how this receptor functions, such as inducing bacterial killing for example, and to determine what the receptor actually recognises on the mycobacteria, and the range of mycobacterial species that can be recognised. Another aspect of these studies, which we will address specifically, is the possibility that our receptor may provide insights for the development of more effective vaccines. Although much of our work will be performed using mouse models, we will also relate our findings to the human system, by showing that the human receptor functions in a similar manner in human cells. In addition, we will also examine the effect of various receptor polymorphisms; small genetic changes in the gene encoding the receptor which may have a significant effect on the receptors function. If we do find such influences, then ultimately we will explore the possibility of an association of these polymorphisms with alterations in disease susceptibility in human populations. We also have evidence that this receptor mediates its cellular functions through a novel mechanism. This mechanism involves transmitting information from the surface to the inside of the cell (intracellular signalling), and is critical for receptor function. Interestingly, we have evidence that our receptor does not transmit the intracellular signal directly, but rather associates with another molecule (an adaptor), which mediates this function. We wish to identify this adaptor molecule, which we will achieve using several different approaches, each of which involves established methodology. Once the adaptor is identified, then subsequent analysis will involve understanding its role in the receptor's function and in host immunity during mycobacterial infections. In sum, we have identified a novel receptor involved in anti-mycobacterial immunity, and the experiments described here will provide substantial and definitive insights into the role and functions of this receptor in both mice and humans.
Technical Summary
C-type lectin receptors (CLR) function in diverse ways and play essential roles in both immunity and homeostasis. We have identified a novel CLR which acts as an activation receptor and which is involved in anti-mycobacterial immunity. We will explore further the functions of this CLR so as to gain novel insights into the protective host mechanisms involved in immunity to Mycobacterium tuberculosis, which remains one the world's most deadliest bacterial infections. For these experiments, we will utilise a receptor-deficient mouse and explore the involvement of this CLR in cellular responses to M. tuberculosis in vitro, and in the induction of innate and adaptive immunity in vivo, using an aerosol model of infection. We will also investigate the functions of this CLR in adaptive immunity, using ovalbumin and ovalbumin-specific T-cell receptor transgenic mice. The ligand(s) and range of mycobacterial species recognised will be determined using cellular assays. We will translate our findings to the human system, by determining the function of the human CLR on primary and transfected cells, and the effect of various identified polymorphisms on receptor function. Ultimately we hope to explore the possibility of an association of these polymorphisms with alterations in disease susceptibility in human populations. We also have evidence that this CLR associates with a novel signalling adaptor molecule, possibly through interactions with its lectin domain. We propose several approaches to identify this adaptor, including methodology involving proteomic analysis and screening a cDNA expression library. Once the adaptor is identified, then subsequent analysis will involve understanding its role in CLR function and in anti-mycobacterial immunity. In sum, we have identified a novel receptor involved in anti-mycobacterial immunity, and the experiments described here will provide substantial and definitive insights into the role and functions of this CLR in both mice and humans.
Planned Impact
Despite over a century of research, Mycobacterium tuberculosis remains one of the deadliest bacterial infections, resulting in over one and a half million deaths each year. Priorities to combat this global problem are the development of new anti-tubercular drugs and a more effective vaccine; both of which depend, in large part, on obtaining a better understanding of the interaction between the host and this bacterial pathogen. We have discovered a novel receptor involved in the recognition of M. tuberculosis and propose here to understand its roles and functions during infection with these organisms. We will also determine the ligand of the receptor, and identify the molecule through which this receptor mediates its intracellular signalling. The results generated from these studies will be of potential benefit to many groups including academia, industry, clinical medicine, and the general public, both nationally and internationally. Our results may also be of significant benefit to third-world countries.
In academia, this research is of potential benefit to many fields including immunology, cell biology, medicinal biochemistry etc. The results of our research will provide substantial new insights into the underlying mechanisms of immunity (in general), anti-mycobacterial immunity (in particular) and host-pathogen interactions, as well as the biology of lectin receptors (in general), pattern recognition receptors (in particular), and intracellular signalling pathways.
In industry, the identification of the ligand of this novel receptor and understanding how the responses triggering by this receptor contribute to the development of adaptive immunity, may suggest novel vaccine adjuvants or alternative strategies for enhancing T-cell responses to subunit and other vaccines. This would be of interest to pharmaceutical companies, as well as those in academia, who are developing vaccines and /or vaccination strategies.
In medicine, greater understanding of the underlying mechanisms of anti-mycobacterial immunity may provide important insights for the future development of novel immunotherapeutic approaches. Furthermore, if we establish a link between receptor polymorphisms and susceptibility to disease, this would be of direct benefit to clinicians and the clinical diagnosis of risk factors associated with tuberculosis. These data may also lead to future alterations in treatment regimens, linked to personalised medicine.
In contrast to many infectious diseases, the general public are very aware of tuberculosis and the health burden of this disease. Therefore, our research is likely to be of general interest to the public, particularly if we find substantial new insights into anti-mycobacterial immunity which leads to novel therapies or diagnostics.
Given the burden of tuberculosis in third-world countries, our identification of host factors and mechanisms which confer resistance or susceptibility and the potential for the development of new therapeutic approaches and /or vaccination strategies would be of substantial benefit to these countries. That part of this research is taking place in such a country will also be of benefit, giving the third world (and South Africa, in particular) a role in the generation of these discoveries.
In academia, this research is of potential benefit to many fields including immunology, cell biology, medicinal biochemistry etc. The results of our research will provide substantial new insights into the underlying mechanisms of immunity (in general), anti-mycobacterial immunity (in particular) and host-pathogen interactions, as well as the biology of lectin receptors (in general), pattern recognition receptors (in particular), and intracellular signalling pathways.
In industry, the identification of the ligand of this novel receptor and understanding how the responses triggering by this receptor contribute to the development of adaptive immunity, may suggest novel vaccine adjuvants or alternative strategies for enhancing T-cell responses to subunit and other vaccines. This would be of interest to pharmaceutical companies, as well as those in academia, who are developing vaccines and /or vaccination strategies.
In medicine, greater understanding of the underlying mechanisms of anti-mycobacterial immunity may provide important insights for the future development of novel immunotherapeutic approaches. Furthermore, if we establish a link between receptor polymorphisms and susceptibility to disease, this would be of direct benefit to clinicians and the clinical diagnosis of risk factors associated with tuberculosis. These data may also lead to future alterations in treatment regimens, linked to personalised medicine.
In contrast to many infectious diseases, the general public are very aware of tuberculosis and the health burden of this disease. Therefore, our research is likely to be of general interest to the public, particularly if we find substantial new insights into anti-mycobacterial immunity which leads to novel therapies or diagnostics.
Given the burden of tuberculosis in third-world countries, our identification of host factors and mechanisms which confer resistance or susceptibility and the potential for the development of new therapeutic approaches and /or vaccination strategies would be of substantial benefit to these countries. That part of this research is taking place in such a country will also be of benefit, giving the third world (and South Africa, in particular) a role in the generation of these discoveries.
People |
ORCID iD |
Gordon Brown (Principal Investigator) |
Publications
Brown GD
(2012)
Hidden killers: human fungal infections.
in Science translational medicine
Brown GD
(2016)
Lectin Receptors Expressed on Myeloid Cells.
in Microbiology spectrum
Brown GD
(2018)
C-type lectins in immunity and homeostasis.
in Nature reviews. Immunology
Drummond RA
(2013)
Signalling C-type lectins in antimicrobial immunity.
in PLoS pathogens
Drummond RA
(2014)
Cutting edge: Failure of antigen-specific CD4+ T cell recruitment to the kidney during systemic candidiasis.
in Journal of immunology (Baltimore, Md. : 1950)
Drummond RA
(2016)
CD4(+) T-cell survival in the GI tract requires dectin-1 during fungal infection.
in Mucosal immunology
Kerscher B
(2016)
Mycobacterial receptor, Clec4d (CLECSF8, MCL), is coregulated with Mincle and upregulated on mouse myeloid cells following microbial challenge.
in European journal of immunology
Kerscher B
(2013)
The Dectin-2 family of C-type lectin-like receptors: an update.
in International immunology
Kerscher B
(2016)
Signalling through MyD88 drives surface expression of the mycobacterial receptors MCL (Clecsf8, Clec4d) and Mincle (Clec4e) following microbial stimulation.
in Microbes and infection
Netea MG
(2012)
Fungal infections: the next challenge.
in Current opinion in microbiology
Description | Dectin-1-mediated suppression of protective anti-mycobacterial immunity |
Amount | £69,730,440 (GBP) |
Funding ID | MR/W025779/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2022 |
End | 08/2025 |
Description | World Class Capital Funding - Spectral Cell Sorter BIGFOOT at the MRC Centre for Medical Mycology |
Amount | £567,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2020 |
End | 03/2021 |
Description | Collaboration with Claire Hoving University of Cape town |
Organisation | University of Cape Town |
Country | South Africa |
Sector | Academic/University |
PI Contribution | The Hoving Team are CO-I on the grant |
Collaborator Contribution | The Hoving Team are CO-I on the grant |
Impact | This collaboration led this the award |
Start Year | 2021 |
Description | Collaboration with Max Guiterrez |
Organisation | Francis Crick Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Max is a collaborator on the grant |
Collaborator Contribution | Max is a collaborator on the grant - he provide preliminary data on intracellular phagosomal pathways |
Impact | none yet - preliminary data for grant |
Start Year | 2021 |
Description | Collaboration with Sho Yamasaki |
Organisation | Osaka University |
Country | Japan |
Sector | Academic/University |
PI Contribution | Sho Yamasaki is a collaborator on this grant. |
Collaborator Contribution | The Hoving Team are CO-I on the grant - he provides MTB ligand indtification |
Impact | None yet other than preliminary data for grant |
Start Year | 2021 |
Description | CLECSF8 discovery |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Press release about or research discoveries. |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.abdn.ac.uk/news/7359/ |
Description | Invited Seminar |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | BSI Greater Manchester Immunology Group's Seminar Series |
Year(s) Of Engagement Activity | 2023 |
Description | Keynote Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Keynote lecture at 2022 London Infections & Immunity Symposium |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.crick.ac.uk/whats-on/the-london-infections-immunity-symposium-2022 |
Description | Plenary Lecture - Siamon Gordon Macrophage symposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation in Oxford at Siamon Gordon's lab reunion. |
Year(s) Of Engagement Activity | 2023 |
Description | Plenary Lecture IUIS immunology Cape Town 2023 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Presentation at IUIS Immunology meeting in Cape Town 2023 |
Year(s) Of Engagement Activity | 2023 |
URL | https://iuis2023.org/ |
Description | Prof Gordon Brown interviewed in the University of Cape Town News following his recognition by the Royal Society |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Prof Gordon Brown was interviewed in the University of Cape Town News following his recognition by the Royal Society |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.news.uct.ac.za/article/-2020-05-08-royal-society-recognises-fungal-infection-researcher |