c-di-AMP为佐剂的重组耻垢分枝杆菌疫苗诱导的固有免疫记忆抗Mtb的保护作用及机制

BCG是结核病惟一疫苗，但其保护不完善。新近发现的固有免疫记忆为机体初次感染后对再感染高反应性的保护性免疫应答。BCG诱导的固有免疫记忆具有特异的抗结核菌保护作用，提示目前提高适应性免疫应答为主的疫苗策略不足之处。建立新的或加强BCG诱导的固有免疫记忆可能获得更有效的疫苗或策略。细菌信号分子c-di-AMP（CDA）可调节细菌生理，诱导固有和适应性免疫，兼具佐剂作用。课题组前期发现，CDA可显著增强BCG及耻垢分枝杆菌（Ms）免疫小鼠再感染后的免疫应答水平，推测CDA为新的固有免疫记忆诱导剂。本研究拟构建CDA分解酶敲除和CDA合成酶过表达的rMs，体内外研究其诱导固有免疫记忆的作用和机制，评价其单独和加强BCG免疫抗结核菌的保护力。本研究有助于阐明CDA诱导固有免疫记忆的作用及机制，有可能获得更安全、更有效并可加强BCG的新疫苗及策略，还为CDA和固有免疫记忆用于其它疫苗的研制奠定基础。

BCG is the only vaccine for tuberculosis (TB), but its protection is not perfect. Recently innate immune memory is found to be a protective immune response to re-infection after primary infection. Innate immune memory induced by BCG has a specific protective effect against Mycobacterium tuberculosis, suggesting that the current vaccine strategy of improving adaptive immune response is insufficient. Establishing new or enhanced BCG-induced innate immune memory may lead to more effective vaccines or strategies. The bacterial signaling molecule c-di-AMP (CDA) regulates bacterial physiology, induces innate and adaptive immunity, and can be used as adjuvant. Our research group found that CDA can significantly enhance the immune response in BCG and M. smegmatis (Ms) immunized mice after reinfection, and speculate that CDA is a new innate immune memory inducer. In this study, we intend to construct rMs with CDA hydrolase enzyme knockout and CDA synthetase overexpression, and study its role and mechanism of inducing innate immune memory in vivo and in vitro, and evaluate its protective effect against M. tuberculosis alone and boosted BCG inoculation respectively. This study will contribute to elucidating the protected effect and mechanism of CDA-induced innate immune memory, and may lead to new vaccines and strategies that are safer, more effective, and can be used to boost BCG. It also lays the foundation for the development of CDA and innate immune memory for other vaccines.