Type I IFN operates pyroptosis and necroptosis during multidrug-resistant A. baumannii infection
Type I IFN operates pyroptosis and necroptosis during multidrug-resistant A. baumannii infection
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I 型干扰素在多重耐药鲍曼不动杆菌感染过程中引起细胞焦亡和坏死性凋亡。
DOI：
10.1038/s41418-017-0041-z
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发表时间：
2018-07-01
影响因子：
12.4
通讯作者：
Qi, Xiaopeng
中科院分区：
文献类型：
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作者：
Li, Yang;Guo, Xiaomin;Qi, Xiaopeng
多重耐药鲍曼不动杆菌是引起医院感染的常见病原体，是肺炎、脑膜炎和菌血症等感染性疾病暴发的主要原因，尤其是在危重患者中。流行病A.鲍曼不动杆菌是一个日益增长的公共卫生问题，因为它对所有现有的抗微生物剂都有抗性，因此需要开发新的治疗方法来产生针对该细菌病原体的有效免疫应答。在这项研究中，我们确定了一个关键的作用，I型干扰素（IFN）在表观遗传调控在A。鲍曼不动杆菌感染并确立了其在多种细胞死亡途径中的核心作用。A.鲍曼不动杆菌感染诱导由凋亡、焦亡和坏死性凋亡组成的混合细胞死亡。机械，A。鲍曼不动杆菌引发TRIF依赖性I型IFN产生，其进而通过KAT 2B介导和P300介导的H3 K27 ac修饰诱导基因Zbp 1、Mlk 1、半胱天冬酶-11和Gsdmd的表达，导致NLRP 3炎性小体活化，并可能促成GSDMD介导的焦亡和MLKL依赖性坏死性凋亡。我们的研究为I型IFN的作用机制提供了新的见解，并为感染性和炎症性疾病提供了潜在的治疗靶点。
Multidrug-resistant Acinetobacter baumannii, a common pathogen responsible for nosocomial infections, is the main cause for outbreaks of infectious diseases, such as pneumonia, meningitis, and bacteremia, especially among critically ill patients. Epidemic A. baumannii is a growing public health concern as it is resistant to all existing antimicrobial agents, thereby necessitating the development of new therapeutic approaches to mount an effective immune response against this bacterial pathogen. In this study, we identified a critical role for type I interferon (IFN) in epigenetic regulation during A. baumannii infection and established a central role for it in multiple cell death pathways. A. baumannii infection induced mixed cell death constituted of apoptosis, pyroptosis, and necroptosis. Mechanically, A. baumannii triggered TRIF-dependent type I IFN production, which in turn induced the expression of genes Zbp1, Mlkl, caspase-11, and Gsdmd via KAT2B-mediated and P300-mediated H3K27ac modification, leading to NLRP3 inflammasome activation, and potentially contributed to GSDMD-mediated pyroptosis and MLKL-dependent necroptosis. Our study offers novel insights into the mechanisms of type I IFN and provides potential therapeutic targets for infectious and inflammatory diseases.