NLRP3介导的c-di-AMP促进抗Mtb免疫保护作用及机制

Mtb在Mφ中长期存活是TB防治难题。NLRP3是机体抗感染免疫重要一环，而Mtb可抑制NLRP3活化，但机制不清。细菌的新信号分子c-di-AMP（cdiAMP）不仅调控细菌基因表达，促进固有和适应性免疫应答，还可激活MφNLRP3。本室研究表明，cdiAMP水平升高的菌株感染Mφ，可促进固有免疫应答，引起细胞死亡，且caspase-1表达增加，感染小鼠体内荷菌数降低。推测：cdiAMP可调节Mtb中作用于 NLRP3分子的表达，并可激活NLRP3，最终促进感染Mtb的免疫清除。本研究拟采用合成和天然的cdiAMP作用于Mφ，明确其对 NLRP3的激活作用；检测cdiAMP对Mtb中作用于NLRP3分子的调节，筛选Mφ中与cdiAMP作用的分子；在此基础上，明确NLRP3介导的cdiAMP促进Mφ和感染动物免疫清除Mtb的作用。本研究将为cdiAMP用于细菌感染的新药物和疫苗研究提供依据

Mycobacterium tuberculosis parasitizes in host macrophages for long time, which is the main barrier of prevention and treatment against TB. The NLRP3 inflammasome plays an important role in anti-infection immune. however M. tuberculosis inhibits NLRP3 by unknown mechanism. c-di-AMP is a new signal molecule in bacterium which has been proved that can induce innate and adaptive immune response, and active NLRP3, as well as regulate bacterium physiological processes. Our previous works had showed that increasing c-di-AMP level in M. tuberculosis induced host innate immune response and more cell death. The expression of caspase-1, one sigh of inflammasome activation, is also increased. Moreover, the bacterium loads were decreased in infected mice organs. Our hypothesis is that c-di-AMP adjusts the expression of M. tuberculosis proteins interactive to NLRP3, and actives NLRP3, which leads the immune clearance of M. tuberculosis. This study will use synthetic and nature c-di-AMP secreted from mycobacterium to transfect macrophages to investigate activation of NLRP3 by c-di-AMP. This study will reveal the molecular mechanism through detecting the regulation of c-di-AMP on M. tuberculosis interacting proteins with NLRP3 and screening macrophage interacting proteins with c-di-AMP. On this bases, the study will detect the effect and efficiency of immune clearance against M. tuberculosis through c-di-AMP by NLRP3 activation. Thus this study will be helpful for c-di-AMP to be used in new drug and vaccine research against M. tuberculosis.