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Title: Hypoxia and the mechanisms regulating inflammatory tissue destruction in tuberculosis
Author: Belton, Moerida
ISNI:       0000 0004 5994 1569
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Mycobacterium tuberculosis (M.tb) causes approximately 2 million deaths a year. There have been few new drugs developed to treat the disease and treatment courses are often complex owing to the emergence of drug resistance and the HIV epidemic. It is unknown whether lesions in human tuberculosis (TB) are hypoxic, nor whether this influences disease pathology. Human TB is characterized by extensive lung destruction driven by host MMPs particularly collagenases such as MMP-1. This thesis describes the investigation of hypoxia in patients with the specific tracer [18F]-Fluoromisonidazole (FMISO). [18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe hypoxia in man. Dynamic imaging and Patlak Ki mapping showed heterogenous levels of oxygenation within and between patients. In M.tb-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 2,800-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilizes HIF-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via TB-dependent networks. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia, and epithelioid macrophages and multi-nucleate giant cells in human TB lung biopsies expressed HIF-1α. HIF-1α blockade including by targeted siRNA inhibited TB-driven MMP-1 gene expression and secretion. Human TB lesions are severely hypoxic and M.tb directly drives HIF-1α accumulation, thereby synergistically increasing collagenase activity leading to cavitation and disease transmission.
Supervisor: Friedland, Jon Sponsor: Medical Resarch Council ; Imperial College Healthcare Charity
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral