Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, Yunnan, China.
Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, 650032, Kunming, Yunnan, China.
Cell Death Differ. 2018 Jul;25(7):1304-1318. doi: 10.1038/s41418-017-0041-z. Epub 2018 Jan 19.
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.
多重耐药鲍曼不动杆菌是一种常见的医院感染病原体，是肺炎、脑膜炎和菌血症等传染病暴发的主要原因，尤其是在重症患者中。流行的鲍曼不动杆菌是一个日益严重的公共卫生问题，因为它对所有现有的抗菌药物都有耐药性，因此需要开发新的治疗方法来对这种细菌病原体产生有效的免疫反应。在这项研究中，我们确定了 I 型干扰素（IFN）在鲍曼不动杆菌感染期间的表观遗传调控中的关键作用，并确定了它在多种细胞死亡途径中的核心作用。鲍曼不动杆菌感染诱导了由细胞凋亡、细胞焦亡和坏死性凋亡组成的混合细胞死亡。在机制上，鲍曼不动杆菌触发了依赖于 TRIF 的 I 型 IFN 产生，进而通过 KAT2B 介导和 P300 介导的 H3K27ac 修饰诱导 Zbp1、Mlkl、caspase-11 和 Gsdmd 的表达，导致 NLRP3 炎症小体的激活，并可能导致 GSDMD 介导的细胞焦亡和 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，并为感染和炎症性疾病提供了潜在的治疗靶点。
