2025-26 Project (Chong & Friedland)

Trained immunity, tissue destruction and novel approaches to treatment in Tuberculosis

SUPERVISORY TEAM

Supervisor

Dr Deborah Chong at City St George’s
Email: dchong@sgul.ac.uk

Co-Supervisor

Professor Jon Friedland at City St George’s
Email: jonfriedland@sgul.ac.uk

PROJECT SUMMARY

Project Summary

Tuberculosis (TB) is one of the of the most prevalent and lethal infectious diseases worldwide, with an estimated 10 million people infected with Mycobacterium tuberculosis (Mtb), the causative agent of TB. The host response to Mtb is a key driver of inflammation and lung tissue destruction. The rise of drug resistance threatens treatment regimens and there are few new therapies. Alternative approaches using host-directed therapies have great potential.

This PhD project offers the exciting opportunity to explore the effects of trained immunity that contribute to inflammation and tissue destruction in TB. The student will integrate into a dynamic research team and use a range of molecular and cellular techniques to assess the impact of trained immune responses in human lung fibroblasts, that modulate TB immunopathology. This project will provide crucial insight into the disease mechanisms in TB and open up new therapeutic targets to stop lung damage in TB patients.

Project Key Words

Tuberculosis, Trained immunity,Fibroblasts, Inflammation

MRC LID Themes

Infectious Disease
Global Health
Translational and Implementation Research

Skills

MRC Core Skills

Quantitative skills
Interdisciplinary skills

Skills we expect a student to develop/acquire whilst pursuing this project

The student will be trained in various techniques focused towards studying immunological and cellular responses. Specific techniques that the student will acquire include:
(i) cell biology techniques, including cell culture of primary fibroblasts, monocyte isolation from blood and functional assays, such as collagenase and collagen deposition assays.
(ii) biochemical techniques including Western blot, qRT-PCR and immunofluorescence microscopy.
(iii) immunological techniques including ELISA and Luminex multiplex assays
(iv) microbiology techniques including culturing Mtb, a category 3 level human pathogen
(v) gene silencing and editing techniques, such as siRNA and CRISPR-Cas9
(vi) verbal and written communication skills to scientific and lay audiences

Routes

Which route/s are available with this project?

1+4 = Yes
+4 = Yes

Possible Master’s programme options identified by supervisory team for 1+4 applicants:

City St George’s – MRes Biomedical Science – Infection and Immunity
City St George’s – MSc Global Health

Full-time/Part-time Study

Is this project available for full-time study? Yes
Is this project available for part-time study? Yes

Location & Travel

Students funded through MRC LID are expected to work on site at their primary institution, meeting – at the minimum – the institutional research degree regulations and expectations. Students may also be required to travel for conferences (up to 3 over the duration of the studentship), and for any required training (for research degree study). Other travel expectations and opportunities highlighted by the supervisory team are noted below.

Primary location for duration of this research degree: City St George’s, London

Travel requirements for this project: None

Eligibility/Requirements

Particular prior educational requirements for a student undertaking this project

Minimum City St George’s institutional eligibility criteria for doctoral study.
BSc at 2.1 or above or MSc in an appropriate related subject area.

Other useful information

Potential Industrial CASE (iCASE) conversion? = No

PROJECT IN MORE DETAIL

Scientific description of this research project

Scientific rationale: Tuberculosis (TB) is the leading cause of death from a single infectious disease, with 10.6 million people infected with Mycobacterium tuberculosis (Mtb). Mtb typically causes pulmonary disease characterised by inflammation and tissue remodelling. Increasing drug resistance threatens international TB programs and new therapeutic approaches are required, harnessing the effective host immune response to infection.

There is increasing evidence highlighting the role of trained immunity in modulating host responses to infection. However, most studies have focused on innate immune cells, such as monocytes. We have shown that lung fibroblasts drive inflammation and tissue destruction in a Mtb-monocyte-dependent network. It is unknown whether priming lung fibroblasts modulates these responses in TB or impacts the subsequent development of novel host-directed therapies.

Project aim: to investigate the regulation and cellular consequences of priming lung fibroblasts that contribute to inflammation and tissue destruction in TB.

Project objectives:
1. Investigate the effect of priming primary human lung fibroblasts (PHLF) on gene expression and secretion of inflammatory mediators, including cytokines and chemokines.
2. Assess the effect of priming PHLF on gene expression and secretion of tissue remodelling enzymes, including matrix metalloproteinases (MMPs) and their inhibitors (TIMPs).
3. Define signalling pathways (e.g. PI3K/Akt/mTOR) regulating inflammatory and remodelling responses.
4. Assess expression of identified key mediators in clinical samples from a Peruvian cohort of TB patients and control subjects.

Methodology: PHLF will be primed with TNF-alpha or IFN-beta for 24h prior to stimulation with conditioned media from Mtb-infected monocytes (CoMTb). After 24, 48 or 72h CoMTb stimulation, secretion and gene expression of MMPs/TIMPs and cytokines/chemokines will be quantified by qRT-PCR or ELISA/Luminex. To assess signalling pathways regulating phenotypical changes, primed PHLF will be pre-treated with specific inhibitors (e.g. LY294002 or rapamycin) to inhibit PI3K/mTOR-induced signalling. Key signalling pathways will be investigated further by siRNA gene-silencing. Lastly, specific mediators or identified key signalling molecules will be quantified in archived plasma or tissue biopsies from Peruvian TB or control patients by Luminex or immunohistochemistry.

Confirmed availability of required materials: Ethical approval is obtained to use archived clinical TB samples or leukocyte cones to isolate monocytes. PHLF are commercially available. Approval to work with Mtb within the CL3 suite is established and training will be provided to the student.

Additional outcomes: The student will receive a strong grounding in molecular and cellular immunological techniques. This project is novel and offers the potential to produce high impact factor publications and the opportunity to present at scientific meetings as part of the PhD experience. The student will contribute to the development of new host-directed therapies for drug-resistant TB.

Potential risk to project & mitigation plans: We do not anticipate any major issues with the described methodology, as planned assays are already established within the host labs. To minimise risks, multiple approaches to knock-down signalling molecules are planned, which will also increase the training of the student. Thus, if inhibitors or siRNA gene-silencing does not achieve full knock-down of signalling molecules, CRISPR-Cas9 will be used (currently being developed in the group).

Additional information from the supervisory team

The supervisory team has provided a recording for prospective applicants who are interested in their project. This recording should be watched before any discussions begin with the supervisory team.

Chong-Friedland recording

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Full list of available projects: MRC LID Projects

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