Inflammasome signalling in Tuberculosis: new routes to host directed therapy

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Host directed therapy (HDT) augments the immune response to drive pathogen clearance and lessen the tissue damage associated with chronic infections such as Tuberculosis. The inflammasome is a multimeric protein complex comprised of intracellular sensor, adaptor, and pro-caspase-1; its assembly leads to processing of the pro-inflammatory cytokine, IL-1beta. Clinical isolates of M. tuberculosis show differential ability to activate the inflammasome and induce IL-1beta processing, and we have shown this can happen in the absence of inflammasome components that were previously thought of as critical sensors. Pharmacological blockade of the inflammasome elicits both anti-inflammatory and anti-microbial activity and can be used in combination with rifampicin.This project will investigate the mechanism of alternative signalling, and establish the components involved in what may constitute a novel inflammasome. Other chemical blockades will be evaluated and synergistic effects with current anti-mycobacterial drugs investigated to devise an alternate regimen to test in vitro and in vivo. The project will cover a range of aspects of molecular biology, immunology and bacteriology, as well as tissue culture and in vivo models such as the wax moth Galleria mellonella.