Abstract
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.
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Acknowledgements
We thank Dr. Feng Shao for the Ifnar−/−, Irf3−/−/Irf7−/−, and Aim2−/− mice, Dr. Shengzhong Duan (Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) for L929 cells, groups of Drs. Jumin Zhou, Yongtang Zheng, Jiali Li (Kunming Institute of Zoology) for technical assistance. This work was supported by the National Key Research and Development Program of China (2017YFD0500300), the Chinese Academy of Sciences (CXJJ-17-M141, Y4ZK111B01, QYZDJ-SSW-SMC012, and Y602381081), the National Natural Science Foundation of China (31701134 and 81701578), Chinese Academy Chinese National Natural Science Foundation (21761142002) and Key Laboratory of Bioactive Peptides of Yunnan Province (AMHD-2018-2).
Author contributions
X. Qi designed the study; Y. Li, X. Guo, C. Hu, Y. Du, C. Guo, D. Wang, W. Zhao, G. Huang, C. Li, Q. Lu, R. Lai, T. Xu, and X. Qi performed experiments and analyzed the data; and X. Qi wrote the manuscript.
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Yang Li and Xiaomin Guo are Co-first author.
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Li, Y., Guo, X., Hu, C. et al. Type I IFN operates pyroptosis and necroptosis during multidrug-resistant A. baumannii infection. Cell Death Differ 25, 1304–1318 (2018). https://doi.org/10.1038/s41418-017-0041-z
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DOI: https://doi.org/10.1038/s41418-017-0041-z
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