Understanding within-patient Mycobacterium tuberculosis genetic diversity to prevent drug-resistance (360G-Wellcome-203583_Z_16_Z)

£380,125

Tuberculosis, caused by Mycobacterium tuberculosis (M.tb), is a major public health problem. Drug-resistant tuberculosis (DR-TB) cases are increasing, creating a significant barrier to disease control. DR-TB is difficult to diagnose and treatment often takes years. M.tb was traditionally thought to be genetically homogenous within the human host, but deep whole genome sequencing (WGS) data have revealed evidence of within-host genetic heterogeneity (GH), particularly in drug-resistance genes. Changing GH patterns over time can cause acquired drug-resistance (ADR). However, how and where in the host GH arises, or how important it is for ADR is not known. I hypothesise that GH represents isolated M.tb subpopulations in separate lung lesions within a patient, and that development of GH is related to local pathology or drug penetration. I will investigate this by WGS of M.tb extracted from resected human lung tissue, and comparing GH to pathology type and local drug concentrations. To evaluate whether GH causes ADR, I will follow patients with newly diagnosed MDR-TB and perform WGS of sequential sputum samples over 6 months for WGS. I will evaluate if ADR is related to baseline GH. Understanding the role of GH in ADR could help develop prevention strategies.

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Grant Details

Amount Awarded 380125
Applicant Surname Nimmo
Approval Committee International Interview Committee
Award Date 2016-06-29T00:00:00+00:00
Financial Year 2015/16
Grant Programme: Title Research Training Fellowship
Internal ID 203583/Z/16/Z
Lead Applicant Dr Camus Nimmo
Partnership Value 380125
Planned Dates: End Date 2020-10-05T00:00:00+00:00
Planned Dates: Start Date 2017-04-05T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Greater London
Sponsor(s) Dr Alexander Pym, Prof Judith Breuer