高原低氧影响小鼠肠黏膜抗感染能力的免疫学机制研究

There is evidence suggesting that hypoxia reduces immune function, which may lead to increased susceptibility to various pathogens, including these infect mucosal surfaces. This notion is supported by the fact that the increased frequencies and severity of various mucosal infections exit in the high plateau regions. In this application we will utilized a well-established infection model, the Citrobacter rodentium-mouse system, a mouse model that has been widely used as an in vivo model of EPEC/EHEC bacterial infection, together with the Hypoxia Chamber. We will investigate whether and how hypoxia impairs host defense and mucosal immunity by examining its impact on innate immunity and subsequent T cell responses (Th1, Th2, Th17 and Treg) in intestinal mucosa, and elucidate the mechanism by which hypoxia alters immune function. It is clear that a better understanding of hypoxia adaptation mechanisms that influence general health of the population in the region is urgently needed. It is expected that the proposed research will provide new insights into the complex interaction between environmental factor (hypoxia) and host immune system in the context of intestinal infection. The results will provide important information about the identity, capacity and mechanistic action of hypoxia involved in host immunosuppression, and may reveal novel, more effective and safer approaches to various mucosal infections in areas where hypoxia is a problem, such as in Qinghai-Tibet Plateau.

组织缺氧会降低机体的免疫功能从而增加机体对病原体的易感性，尤其是侵袭黏膜的病原体，然而目前关于低氧对免疫系统的影响以及宿主防御病原微生物的认识还非常有限。本研究通过建立人肠致病性大肠杆菌（EPEC）和肠出血性大肠杆菌（EHEC）特异性小鼠肠道C.rodentium感染模型，探讨低氧影响机体固有免疫、T细胞（Th1、Th2、Th17）功能及免疫调节细胞（Treg）功能而改变宿主抗肠道感染能力的免疫学机制，着重研究不同低氧时间影响此类病原体侵袭黏膜关键保护性免疫细胞（DCs，Mac, Th1，Th2, Th17，Treg) 的功能，同时研究这些改变影响宿主对肠道细菌的易感性，探讨其免疫调节机制。该研究对探讨高原低氧影响机体抗感染能力的免疫学机制意义重大，可为高原感染性疾病的救治和新型药物的开发提供重要的理论指导。

缺氧会降低机体的免疫功能从而增加机体对病原体的易感性，尤其是侵袭黏膜的病原体，然而目前关于高原低氧对免疫系统的影响以及宿主防御病原微生物的认识还非常有限。本研究通过建立人肠致病性大肠杆菌（EPEC）和肠出血性大肠杆菌（EHEC）特异性小鼠肠道C.rodentium 感染模型，探究了低氧影响机体固有免疫、T 细胞（Th1、Th2、Th17）功能及免疫调节细胞（Treg）功能而改变宿主肠道抗感染能力的免疫学机制，着重研究了低氧影响此类病原体侵袭黏膜关键保护性免疫细胞（DCs，Mac, Th1，Th2, Th17，Treg) 的功能，同时研究了这些改变影响宿主对肠道细菌的易感性，探讨其免疫调节机制。通过流式细胞术、ELISA、细胞过继转移等免疫学技术，PCR 和Western Blot 等分子生物学技术以及抗体中和等实验方法，探讨了高原低氧影响机体免疫功能和改变宿主抗肠道感染能力的免疫学机制。课题组成功建立了低压低氧C.rodentium感染小鼠模型，通过研究发现低压低氧可通过影响Th1、Th17免疫反应以及黏膜固有层树突状细胞（DCs）的成熟、分化状态，进而影响T细胞免疫功能发挥。上述结果揭示高原低氧环境通过影响机体免疫调节从而改变了机体的抗感染能力，研究结果将为高原感染性疾病的救治提供重要的理论指导。通过该项目的实施，在人才培养方面组建了青海大学医学院“高原医学免疫学研究创新团队”，培养了骨干教师2名、博士研究生2名、硕士研究生3名、留学生1名。项目资助发表SCI 文章2篇，中文1篇，待发表论文2篇。