Inflammasome signalling in Tuberculosis: new routes to host directed therapy

宿主定向治疗(HDT)增强免疫反应，推动病原体清除，减少与结核病等慢性感染相关的组织损伤。炎症体是一种多聚体蛋白复合体，由细胞内感受器、接头和caspase-1原组成；它的组装导致促炎细胞因子IL-1β的处理。结核分枝杆菌的临床分离株显示出激活炎症体和诱导IL-1β处理的不同能力，我们已经证明，在没有以前被认为是关键传感器的炎症体成分的情况下，这可能会发生。对炎症体的药理阻断可产生抗炎和抗微生物活性，并可与利福平联合使用。本项目将研究替代信号的机制，并建立可能构成新型炎症体的成分。将对其他化学阻滞剂进行评估，并研究与现有抗分枝杆菌药物的协同作用，以设计一种替代方案进行体外和体内试验。该项目将涵盖分子生物学、免疫学和细菌学的一系列方面，以及组织培养和活体模型，如蜡蛾Galleria mellonella。

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.