I型干扰素信号途径及其介导的细胞死亡在耐药性鲍曼不动杆菌感染中的作用机制研究

Multidrug-resistant Acinetobacter baumannii (A.baumannii), one of the most common pathogens responsible for nosocomial infections, is the main cause for outbreaks of infectious diseases including pneumonia, meningitis and bacteremia, especially among critically ill patients. The epidemic A.baumannii is an increasing threat because of the limited therapeutic options to deal with its resistance to every antimicrobial agent available. Development and discovery of new therapeutic approaches to recapitulate an effective immune response for defending A.baumannii infection are essential. Our previous data showed type I interferon is critical for host defense against A.baumannii infection. Here we proposed using primary BMDMs and knock out mice infection model to study： 1) The mechanism of IFN-I production during infection; 2) the role of IFN-I in cell death induced by A.baumannii infection; 3) the role of IFN-I in immune cell differentiation and migration in response to A.baumannii infection. Our goal is to identify the central role of IFN-I in cell death during A.baumannii infection. Thus, our study is not only important for further understanding the mechanism of infection-induced immune response, but also will provide alternative approaches for preventing and curing multi-drug resistant bacterial infections.

鲍曼不动杆菌（Acinetobacter baumannii）是一类广泛存在的革兰氏阴性细菌，能够通过呼吸道等多种方式传播。耐药性鲍曼不动杆菌已成为医院内流行感染的主要细菌之一，其危害性在免疫力低下人群中尤其严重。目前鲍曼不动杆菌感染诱导的宿主免疫反应仍研究较少。 本项目前期研究发现，I型干扰素信号途径在宿主抵抗耐药性鲍曼不动杆菌感染中发挥重要作用。基于前期研究基础，本项目拟利用耐药性鲍曼不动杆菌建立的突变体小鼠肺部感染模型及原代细胞感染模型，集中对鲍曼不动杆菌感染过程中以下问题进行考察：1）I型干扰素的产生及效应；2）I型干扰素对细胞死亡的调控及其分子机制；3）I型干扰素对免疫细胞应答的调控及作用机制。该研究不仅对于感染免疫领域的机制研究具有促进作用，并且对于探索针对耐药性病原菌的新型策略具有战略意义。

本课题开展了鲍曼不动杆菌感染诱导I型干扰素信号激活和调控机制，以及I型干扰素信号介导的炎症小体激活和宿主防御机理研究。我们的研究发现鲍曼不动杆菌会利用外膜囊泡通过TRIF通路诱导宿主I型干扰素信号激活，I型干扰素会进一步调控细胞死亡路径关键基因表达，促进鲍曼不动杆菌感染诱导的细胞焦亡、细胞坏死和凋亡发生，诱导炎症反应在宿主防御鲍曼不动杆菌感染中发挥正向调控作用。此外，我们的研究还发现3个关键蛋白HECTD3、 RNF220和HUWE1调控了病原菌感染诱导I型干扰素信号和炎症小体的激活过程；并确定了炎症相关的糖酵解代谢路径在宿主防御鲍曼不动杆菌感染中发挥重要作用。研究成果在JCI和 CDD等国际期刊发表研究论文8篇，拓展了人们对鲍曼不动杆菌致病机制的理解，促进了感染与免疫的基础理论研究，对于探索针对耐药性病原菌的新型干预策略具有重要意义。