Investigating the impact of lactate on the macrophage response in tuberculosis disease


   Institute of Inflammation and Ageing

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  Dr Alba Llibre Serradell, Prof Claudio Mauro  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Additional supervisor Professor Andrea Cooper, University of Leicester

Informal enquiries to be sent to Dr Alba Llibre ([Email Address Removed]) and Prof Claudio Mauro ([Email Address Removed])

Person Specification

Applicants should have a strong background in immunology, and ideally a background in infectious diseases and/or metabolism. They should have a commitment to research in immunology and infection and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

We are seeking talented, hard-working and motivated students with a passion for research in Immunology, Metabolism and Infectious diseases to join the team led by Dr Alba Llibre (https://www.birmingham.ac.uk/staff/profiles/inflammation-ageing/llibre-alba.aspx).

Tuberculosis (TB) is a pathogen infecting macrophages in the lung where it can persist for decades. It is a major global public health challenge affecting 10 million people in 2019, with 1.4 million deaths, despite vaccination and available treatments. The emergence of multidrug resistant TB and new antibiotic resistance strains exacerbate disease burden. Macrophages are capable of bactericidal activity towards Mycobacterium tuberculosis (M.tb), an essential mechanism for infection control. To design novel host-directed therapies, a better understanding of how M.tb infection impacts host immune responses is crucial.

Lungs of M.tb-infected hosts are lactate-rich environments. We were among the first to show that lactate is an active signalling molecule and that macrophages respond to it through different transporters and receptors with the activation of pro- or anti-inflammatory responses, depending on the context. We have a poor understanding of how lactate shapes macrophage responses to M.tb and how this dictates infection outcome. The current hypothesis is that lactate in TB lungs promotes macrophage-mediated M.tb killing. To this end we need to investigate the impact of lactate on macrophage function and M.tb infection resolution. Exploiting this knowledge could be key for the design of new TB therapies, which are an urgent, unmet need.

The overarching aim of this project is to investigate the impact of lactate on macrophage function and M.tb infection resolution by:

1. Dissecting the molecular mechanisms by which lactate drives macrophage function.

2. Assessing the therapeutic potential of targeting lactate sensing to treat TB disease.

The candidate will learn a wide array of molecular biology techniques (e.g. Flow cytometry, ELISA, tissue culture) and be trained in cutting-edge microscopy techniques, as well as in the ex vivo precision cut lung tissue slices (PCLTS) infection model (a novel and unique tool to study local human tissue responses). Through an interdisciplinary approach, combining the fields of clinical microbiology, immunology and metabolism and big data, the candidate will focus on answering the urgent question of how immune-metabolic responses impact the host’s ability to resolve M.tb infection. This project represents a unique opportunity to ease the pathway towards novel treatments for an ancient disease, using cutting-edge science in an excellent, supportive research environment.

Working environment and positive research culture

We understand a positive research culture ai an essential ingredient of both research excellence and wellbeing of researchers. We have worked hard to create a diverse, inclusive, connected, supported and resilient team. We make sure every team member has ownership of their project while offering the required guidance and support. The candidate will be offered critical, constructive criticism on a regular basis, and full understanding and support of research challenges will be provided.

 How to apply

Please click on the institution website which will direct you to the MRC AIM website which provide full application details including the application forms. Please ensure your application is submitted by the deadline of midday (GMT) Friday 12 January 2024 as late applications will not be considered.

Biological Sciences (4) Medicine (26)

Funding Notes

This is a fully funded studentship provided by the Medical Research Council.
If you are successful, you will receive a stipend (currently £18,622 per year for 2023/24) and a tuition fee waiver for 4 years.
Successful candidates will also receive an allowance for a laptop, a travel and conference allowance and an allowance for laboratory/PhD running costs.

References


Llibre A, Smith N, Rouilly V, Musvosvi M, Nemes E, Posseme C, Mabwe S, Charbit B, Kimbung-Mbandi S, Filander E, Africa H, Saint-André V, Bondet V, Bost P, Mulenga H, Bilek N, Albert ML, Scriba TJ, Duffy D. Tuberculosis impacts immune-metabolic pathways resulting in perturbed IL1 responses. Front Immunol. 2022.
Certo M*, Llibre A*, Lee W, Mauro C. Understanding lactate sensing and signalling. Trends Endocrinol Metab 2022.
Llibre A*, Grudzinska FS*, O’Shea MK, Duffy D, Thickett DR, Mauro C, Scott A. Lactate cross-talk in host-pathogen interactions. Biochem J. 2021.
Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T, D'Acquisto F, Bland EJ, Bombardieri M, Pitzalis C, Perretti M, Marelli-Berg FM, Mauro C. Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions. PLoS Biol. 2015.
Pucino V, Certo M, Bulusu V, Cucchi D, Goldmann K, Pontarini E, Haas R, Smith J, Headland SE, Blighe K, Ruscica M, Humby F, Lewis MJ, Kamphorst JJ, Bombardieri M, Pitzalis C, Mauro C. Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring. Cell Metab. 2019.

Where will I study?

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