Inflammasome signalling in Tuberculosis: new routes to host directed therapy

宿主定向治疗（HDT）增强免疫反应，以驱动病原体清除并减轻与慢性感染（如结核病）相关的组织损伤。炎性小体是一种多聚体蛋白复合物，由细胞内传感器、接头和前caspase-1组成；它的组装导致促炎细胞因子il -1 β的加工。临床分离的结核分枝杆菌在激活炎性小体和诱导il -1 β加工方面表现出不同的能力，我们已经证明，在缺乏炎性小体成分的情况下，这种情况可能发生，而炎性小体成分以前被认为是关键的传感器。对炎症小体的药物阻断可引起抗炎和抗微生物活性，并可与利福平联合使用。该项目将研究替代信号传导的机制，并确定可能构成新型炎性体的成分。将评估其他化学阻断剂，并研究与当前抗分枝杆菌药物的协同作用，以设计一种替代方案，在体外和体内进行试验。该项目将涵盖分子生物学、免疫学和细菌学的一系列方面，以及组织培养和蜡蛾等体内模型。

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.