JNK1负调控抗真菌天然免疫反应的分子机制研究

Opportunistic fungal infection in ICU remains the leading death cause for immune-compromised patients, such as HIV, cancer and organ transplant patients. Fungi also cause systemic infections in immune-competent hosts and the number of infections is increasing. There is pressing need to develop anti-fungal immune therapy because of the drug resistance and toxic effect. C-type lectin receptor and NF-kB pathway has been demonstrated to be the key events in how host immune system defense against fungi infection during the last two decades. However, little negative factor during the fungal immunity has been identified, which could be the ideally drug to treat fungal infection. .Our recent studies focus on the role of C-type lectin receptors and its downstream immune-related signal pathway, and several papers were published on the top journal in Immunology field. Our preliminary studies show that JNK may contribute to the negative regulation of the anti-fungal innate immune responses. JNK1, but not JNK2 knockout mice is more resistant to the fungal infection, and JNK1 deficiency-associated protective effect is dependent on the up-regulated expression of CD23, which correlates with higher level of nitric oxide production. Therefore, this proposal will focus on the function of JNK in the anti-fungal immune response, identify and characterize the molecular mechanism how JNK1 regulate the fungal infection process, determine if JNK inhibitors can be used as therapeutic agents to treat fungal infection and the mechanism. Together, these lines of investigation will reveal molecular mechanisms of the negative regulation of host innate immune system following fungal infection. Results from these lines of investigation will provide the molecular insight for designing therapeutic agents against fungal infection.

真菌感染是造成免疫缺陷病人死亡的首要因素，临床抗真菌药物有限及真菌的超强耐药性导致其感染防治面临严峻挑战。免疫系统在识别及清除真菌过程中发挥关键作用。关于宿主免疫细胞表达的C型凝集素受体感知真菌成份激活机体免疫反应的研究目前已取得一定进展，但涉及真菌免疫反应中负性调控因子的研究基本为空白，这些负性调控因子更易开发为药物用于治疗。.申请人近年关注C型凝集素受体相关的免疫学研究并有多项成果在权威免疫学杂志上发表。申请人最近发现，JNK信号通路可负向调节真菌免疫反应，JNK1敲除小鼠感染致死率显著降低，可能与C型凝集素受体CD23上调相关。本项目拟解析JNK在真菌免疫中的作用，系统阐明JNK信号通路影响真菌免疫的分子机制，探索JNK抑制剂作为药物治疗真菌感染的可行性及机理。此研究将弥补目前国内国际上关于真菌免疫反应中负性调控因子研究领域的空白，为日益严重的真菌感染疾病提供新的分子靶标和治疗策略。

真菌感染是造成免疫缺陷病人死亡的首要因素，临床抗真菌药物有限及真菌的超强耐药性导致其感染防治面临严峻挑战；C型凝集素受体介导的信号通路在免疫系统对真菌识别及清除过程中发挥关键作用。本项目系统阐明了JNK信号通路影响真菌免疫的分子机制，探索JNK抑制剂作为药物治疗真菌感染的可行性及机理；探究了CD23在真菌感染免疫反应中的作用及相关胞内信号通路的活化，取得了一系列重要研究成果。此研究将弥补目前国内国际上关于真菌免疫反应中负性调控因子研究领域的空白，为日益严重的真菌感染疾病提供新的分子靶标和治疗策略。.通过此项目支持，已发表了和课题密切相关的项目负责人为通讯作者的2篇高水平原创性学术论文，包括1篇Nature Medicine和1篇Journal of Immunology，获得了1项发明专利授权；还发表了基金标注与本研究相关的5篇论文。培养了5名博士毕业生和2名博士后出站。