Huo Caiyun, Li Yuli, Tang Yuling, Su Ruijing, Xu Jiawei, Dong Hong, Hu Yanxin, Yang Hanchun
Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Beijing Key Laboratory of Traditional Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing 102206, China.
Int J Mol Sci. 2025 Apr 27;26(9):4162. doi: 10.3390/ijms26094162.
Influenza A virus (IAV) infection causes considerable morbidity and mortality worldwide, and the secondary bacterial infection further exacerbates the severity and fatality of the initial viral infection. Mitophagy plays an important role in host resistance to pathogen infection and immune response, while its role on pulmonary epithelial cells with viral and bacterial co-infection remains unclear. The present study reveals that the secondary infection significantly increased the viral and bacterial loads in human lung epithelial cells (A549) during the initial H1N1 infection. Meanwhile, the secondary infection triggered more intense mitophagy in A549 cells by activating the PINK1/Parkin signaling pathway. Notably, mitophagy could contribute to the proliferation of pathogens in A549 cells via the inhibition of cell apoptosis. Furthermore, based on an influenza A viral and secondary bacterial infected mouse model, we showed that activation of mitophagy was conducive to the proliferation of virus and bacteria in the lungs, aggravated the inflammatory damage and severe pneumonia at the same time, and eventually decreased the survival rate. The results elucidated the effect and the related molecular mechanism of mitophagy in pulmonary epithelial cells following IAV and secondary infection for the first time, which will provide valuable information for the pathogenesis of virus/bacteria interaction and new ideas for the treatment of severe pneumonia.
甲型流感病毒（IAV）感染在全球范围内导致相当高的发病率和死亡率，而继发性细菌感染会进一步加剧初始病毒感染的严重程度和致死率。线粒体自噬在宿主抵抗病原体感染和免疫反应中起重要作用，但其在病毒和细菌共同感染的肺上皮细胞中的作用仍不清楚。本研究表明，在初始H1N1感染期间，继发性感染显著增加了人肺上皮细胞（A549）中的病毒和细菌载量。同时，继发性感染通过激活PINK1/Parkin信号通路在A549细胞中引发更强烈的线粒体自噬。值得注意的是，线粒体自噬可通过抑制细胞凋亡促进病原体在A549细胞中的增殖。此外，基于甲型流感病毒和继发性细菌感染的小鼠模型，我们发现激活线粒体自噬有利于病毒和细菌在肺部的增殖，同时加重炎症损伤和严重肺炎，并最终降低存活率。该结果首次阐明了IAV和继发性感染后线粒体自噬在肺上皮细胞中的作用及相关分子机制，这将为病毒/细菌相互作用的发病机制提供有价值的信息，并为严重肺炎的治疗提供新思路。
