Investigating the dual impact of lactate on the pathogen and the host during Mycobacterium tuberculosis infection

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 public health challenge; in 2021, 10.6 million people fell ill with TB and 1.6 million died. The causative agent of TB is Mycobacterium tuberculosis (M.tb) and its primary target are lung macrophages. Multidrug resistant TB is a global health threat, and we urgently need new drugs to fight it.

Lungs of M.tb-infected hosts are lactate-rich environments. Lactate is an active signalling molecule and macrophages respond to it through different transporters/receptors. M.tb can use lactate as a fuel source, and to synthesise aminoacids. There has been a very strong selective pressure on the lactate dehydrogenase lldD2 gene, suggesting a key role for survival. Furthermore, lactate shapes mycobacterial transcription, resulting in changes in cell wall lipids and virulence factors.

We have a poor understanding of how lactate shapes macrophage responses to M.tb, and how it impacts mycobacterial fitness, both key factors that dictate infection outcome. Based on preliminary data, our working hypothesis is that lactate in TB lungs strengthens the macrophage’s ability to kill M.tb, and that modulating host and/or mycobacterial responses to lactate has therapeutic potential.

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

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

We have identified two potential mechanisms by which lactate drives macrophage responses:

a)   GPCR signalling: The candidate will use Bioluminescent and fluorescence resonance energy transfer (BRET/FRET) and single molecule localisation microscopy (SMLM) to characterise lactate-elicited signalling cascades through GPR132/GPR81 in cell-line derived and primary macrophages.

b)   Lipid droplet (LD) formation: LD-rich foamy macrophages are a hallmark of TB granulomas. Exposing lung macrophages to lactate results in a specific cytokine secretion profile, which is LD-dependent. The candidate will mechanistically elucidate the links between lactate-LDs and cytokine shifts. Mass spectrometry, CFUs/MGIT assays and in vitro experiments using inhibitors of LD formation will be employed.

2. Elucidating the mechanisms behind lactate’s impact on mycobacterial fitness.

To study the impact of lactate on M.tb growth and fitness, we will take a two pronged-approach. We will test the effects lactate on cell envelope lipid content using a set of two-dimensional thin-layer chromatography (2D-TLC) systems designed to show the full profile of M.tb lipids including those involved in virulence. In parallel, we will conduct fitness and biochemical studies using a lldD2 null-mutant of M.tb. Changes in growth patterns (in vitro and in vivo), and a comparative lipid profile will be conducted using wild type, mutant and complemented strains, grown with or without lactate.

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

To study local tissue responses, the candidate will use an ex vivo precision cut lung tissue slices (PCLTS) infection model which will be applied to human lung tissue (collaboration with Prof Thickett/Dr Scott). The model retains tissue architecture while maintaining native interactions between different pulmonary cell types. Lung slices will be challenged with the virulent M.tb H37Rv. CFU/MGIT assays, specific inhibitors of lactate pathways (ie. LD formation, GPCR signalling), ELISA/Luminex and immunofluorescence will be used to understand drivers of infection control.

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.

Multidisciplinary and new ways of working

The proposed project is interdisciplinary at its core, combining the fields of immunology, microbiology, metabolism and respiratory science. We strongly believe a joined effort from multiple angles is the one way to tackle complex biological questions. Delivery of this project will rely on the use of cutting-edge methodologies and experimental systems, including high resolution microscopy and a human lung slice M.tb-infection model.

Project techniques

The candidate will have the opportunity to learn and master a wide range of techniques, including cell culture, PBMCs and alveolar macrophage isolation, flow cytometry, PCR, ELISA/Luminex, immunohistochemistry and immunofluorescence. For mechanistic studies, bioluminescent and fluorescence resonance energy transfer (BRET/FRET), mass spectrometry, and mycobacterial growth inhibition assays will be employed. Crucially, the candidate will be involved the development of a M.tb infection model using human lung slices, a precious and scarce resource. The candidate will also be trained in mycobacterial molecular biology, mycobacterial growth methods in a BSL3 setting, and biochemical analytical techniques to study mycobacterial cell wall physiology.

Working environment and positive research culture

We understand a positive research culture as 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.

Person specification 

Applicants should have a first or upper second-class degree in a relevant scientific discipline, and be self-funded or have typically applied for, or secured funding for their studies from their government, employer or associated charitable organisations.

How to apply

Informal enquiries should be directed to Dr Alba Llibre (a.llibre@bham.ac.uk) and Dr Apoorva Bhatt (a.bhatt@bham.ac.uk).

To apply, please follow the link and instructions below:

https://sits.bham.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=FR608G&code2=0004

This Link will take you to the admissions portal.

Within the ‘Research Details’ tab, enter the title of the project they are applying for, along with the name of the project’s supervisor (Dr Alba Llibre).

Within the ‘Funding Information’ tab (standard projects), choose ‘University of Birmingham advertised scholarship’ and ‘BBSRC Midlands Integrative Biosciences Training Partnership (MIBTP) DTP’

You will need to submit you CV as part of the application.

Applicants who have been successfully shortlisted for interview will be contacted by mid-February 2025.

Interviews for successfully shortlisted applicants will be held during the first two weeks in March 2025. 

Additional information

For more information in the Midlands Integrative Biosciences Training Partnership (MIBTP) please visit

https://warwick.ac.uk/fac/cross_fac/mibtp/