纳米硒缓释棕榈油酸靶向“肠-肺轴”的抗结核免疫功能与机理

结核是第1致死性传染病，我国结核疫情严重，遏制结核蔓延迫在眉睫。团队长期从事结核深层次病理机理及防治新技术研究。如何重构结核发生发展及传统抗痨治疗伴随或促进的肠道微生态紊乱和免疫稳态失衡是结核控制的难题与焦点。我们前期发现抗结核保护性肠道菌优势代谢物棕榈油酸（POA）可显著改善“肠-肺轴”免疫稳态并有效控制结核感染及其恶性病理损伤。但是，仍亟需进一步提高POA在肠黏膜界面的免疫稳态调控时空效能从而为其成功开发奠定更扎实基础。为此，在团队新近开发的纳米硒多维度高效胞内结核清除技术基础上，进一步构建POA-纳米硒缓释递送系统，全面分析POA-纳米硒是否及如何增强POA对肠道微生态及其代谢谱以及肠内、外免疫稳态调控的时空效能，深入揭示其抑制结核感染和病损的功能、机理与临床意义，从而为靶向干预“肠-肺轴”而调谐抗结核免疫稳态进而抑制结核感染及其恶性病损提供新范例，为结核/耐药结核的治疗提供新策略。

Tuberculosis (TB) remains a deadly infectious disease with extremely high morbidity and mortality in China, which requires the development of new treatment strategy. We have long been engaged in the research of the underlying mechanisms of anti-TB immunity and strategy. How to reconstruct the intestinal microecology disorder and disbalance of immunological homeostasis induced by TB and current anti-TB drug treatment remains the most focused and challenged issue for TB treatment. Our previous work has demonstrated a metabolite palmitoleic acid (POA), derived by an anti-TB gut bacteria, is capable of manipulating gut-lung immune interaction axis to confer immune protection against TB infection and pathological damage. However, the spatial and temporal effects of POA on the surface of intestinal mucosa still need to be further improved. We have previously developed a selenium nanoparticle system based intracellular Mtb clearance strategy with multiple anti-TB functions and found that this selenium nanoparticle system could significantly improve the spatial and temporal effects of drugs. Therefore, this project proposal plans to construct POA-selenium nanoparticles (POA@NanoSe), which is expected to inhibit Mtb infection and alleviate Mtb induced pathological damage in vivo. We will systematically analyze whether and how POA-Se NPs could enhance the spatial and temporal effects of POA on the intestinal microecology with its metabolism, intestinal and extra-intestinal immunity homeostasis, following by the deeply exploration of the function, mechanism and clinical significance on the inhibition of Mtb infection and Mtb induced pathological damage in vivo. This work will provide a novel prototype about intervening gut-lung axis to regulate immunological homeostasis for the control of Mtb infection and its associated pathological damage, which is also expected to offer new strategies for the treatment of TB and particularly drug-resistant TB.