Human TB granulomas as targets for host-directed therapies and prediction of disease progression (360G-Wellcome-206751_Z_17_Z)

£626,404

Tuberculosis remains a leading global health problem that is aggravated by drug resitance. Thus, envisioned eradication of this disease requires better therapeutic and diagnostic strategies. Identification of host factors associated with the pathological damage may accelerate discovery of adjunct host-directed therapies and predictive biomarkers for TB disease. The goal of this project is to characterize proteins that are causally connected to granuloma caseation during TB infection. In their solid form, granulomas can control infection by restricting the pathogen to the center. However, granulomas can necrotize and develop caseum, a pathological feature that facilitates extensive lung destruction. In our recently published study, we demonstrated that proteomics can be used to determine the history of molecular events that help shape the granuloma. We also found that important factors required for TB granuloma development or progression are regionally distributed, with pro-inflammatory proteins enriched in the caseum. I propose to use molecular histology tools, including immunohistochemistry and confocal microscopy to investigate mechanisms underlying caseous necrosis and macrophage necrotic breakdown; to develop host-directed methods to decrease the resultant damage; to characterize macrophage functional diversity in granulomas; and to develop predictive biomarkers that can be used to diagnose those at highest risk for caseation.

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Grant Details

Amount Awarded 626404
Applicant Surname Marakalala
Approval Committee International Interview Committee
Award Date 2017-06-19T00:00:00+00:00
Financial Year 2016/17
Grant Programme: Title International Intermediate Fellowship
Internal ID 206751/Z/17/Z
Lead Applicant Dr Mohlopheni Marakalala
Partnership Value 626404
Planned Dates: End Date 2019-02-28T00:00:00+00:00
Planned Dates: Start Date 2017-10-01T00:00:00+00:00
Recipient Org: Country South Africa
Region International
Sponsor(s) Prof Valerie Mizrahi