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Using Host-Pathogen Interaction Dynamics to Identify Novel Drug Targets in Clinically Relevant Mycobacterium tuberculosis Isolates

Code: BC-DTP_2026_15

Title: Using Host-Pathogen Interaction Dynamics to Identify Novel Drug Targets in Clinically Relevant Mycobacterium tuberculosis Isolates

Primary Supervisor: Dr Divya Tiwari

Email: d.tiwari@qmul.ac.uk

Institute: Blizard Institute 

Secondary Supervisor: Professor Adrian Martineau

Email: a.martineau@qmul.ac.uk 

Institute: Blizard Institute

 

Lay Summary:

Tuberculosis (TB) is one of the world’s leading infectious killers, caused by Mycobacterium tuberculosis (Mtb), a bacterium able to persist for years inside the body by hiding within macrophages, the very immune cells meant to destroy it. Although new TB drugs have been developed, Mtb rapidly acquires resistance, making it necessary to develop more effective treatments.

Mtb exists as different types or ‘strains’—some infect humans (‘clinical strains’), while others are used for research (‘laboratory strains’). This project investigates how different clinical strains survive inside the human lungs. Most research relies on laboratory strains, which do not fully represent those infecting patients. By studying a large collection of clinical isolates from people with TB affecting the lungs and other organs, we will improve understanding of how strains differ in their interaction with host immunity.

We will infect different macrophage types that mimic the varying environments Mtb encounters in the body. Using advanced techniques, we will determine which bacterial genes are activated during infection, how host cells respond and validate these findings in 3D-lung-like models that better mimic human tissue.

By comparing many strains across multiple conditions, this work will identify a core set of bacterial genes essential for Mtb survival that can be targeted for new TB drugs. We will also pinpoint strain-specific factors linked to severe or disseminated disease, informing future vaccine development.

Ultimately, this research will generate a roadmap of how Mtb persists inside human cells, guiding the development of more precise and widely effective TB treatment strategies.

Aims:

The overall aim of this proposal is to identify a core bacterial gene expression signature that enables Mtb survival across diverse, physiologically relevant macrophage environments by integrating clinically diverse strains with advanced 2D and 3D tissue-like models.

Aim 1: Comparative Virulence Factor Profiling. Characterizing lipid and protein virulence factors across clinical isolates, Beijing strains, and H37Rv to establish baseline differences in molecules that interface with host immunity.

Aim 2: Niche-Specific Gene Signature Mapping. Identifying strain-specific and niche-specific bacterial and host transcriptomes across varied macrophage states using dual RNA sequencing to understand how bacterial adaptation to distinct host niches shapes survival and immune responses.

Aim 3: Validation of Gene Signatures in Complex Physiological Models.

Validating bacterial gene signatures in granuloma organoids and precision-cut lung slices (PCLS) to ensure translational relevance in multi-cellular, tissue-like environments.

Aim 4: Validating the Biological Function of Candidate Virulence Genes.

Experimental validation of the role of candidate genes in bacterial virulence using genetically modified strains (deletion/knockdown) in virulent strains.

References:

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  • Remot A, Carreras F, Coupe A, Doz‑Deblauwe E, Boschiroli ML, Browne JA, et al. Mycobacterial infection of precision‑cut lung slices reveals Type 1 interferon pathway is locally induced by Mycobacterium bovis but not M. tuberculosis in a cattle breed. Front Vet Sci. 2021;8:696525.
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