Research

Under the theme of host-pathogen interactions, we investigate the effect of Mycobacterium tuberculosis (M.tb) on the secretion of human proteases from host cells which can cause tissue destruction and cell death. There are 5 distinct classes of proteases which are classified by the mechanism of catalysis: aspartic, metallo, cystein, serine and threonine proteases. We profile the proteases found in active TB patients and investigate host proteases in extra-pulmonary TB including central nervous system TB while evaluating for diagnostic and/or prognostic value to TB treatment outcome. Using cellular and murine models, we focus on the regulation of these proteases from host cells including mononuclear cells, neutrophils, and parenchymal cells. Intracellular signalling pathways and transcription factors are interrogated to determine if there are switch points by which potential therapeutic agents can be administered to suppress the detrimental effects of human proteases on TB-associated tissue destruction.

Under biomarker discovery, we focuse on identifying M.tb circulating cell-free DNA (cfDNA) in TB patients. cfDNA is circulating DNA fragments from degenerating cells found in body fluids including blood and urine. cfDNA has been used to diagnose cancer, measure tumour burden and monitor recurrence of tumours including Epstein-Barr virus associated nasopharyngeal cancers. We extend this concept to TB diagnosis and quantifying M.tb bacterial load in TB patients. This proof-of-concept study will evaluate M.tb cfDNA to detect and monitor bacterial load in TB patients by clinical samples obtained by non-invasive means. The long term aim is to develop a point-of-care nuclear acid based test that will promptly diagnose TB and simultaneously monitor TB treatment. More recently, we have also started a project in BIGHEART investigating a point-of-care test for rapid pathogen diagnosis.

Under host-directed therapies, we explore existing drugs that have potential to modulate TB treatment outcome. We investigate repurposed drugs such as doxycycline, a licensed MMP inhibitor as an adjunct therapy to TB treatment in TB patients. Concurrently, with our animal models, we further pre-clinical data to evaluate the use of host-directed therapeutic agents to suppress immunopathology in TB. This model would provide preliminary data for potential therapies to be tested in human TB patients in future.