Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610000, People's Republic of China.
Reproductive & Women-Children Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, People's Republic of China.
J Microbiol. 2023 Aug;61(8):777-789. doi: 10.1007/s12275-023-00076-y. Epub 2023 Oct 4.
Co-infection of respiratory tract viruses and bacteria often result in excess mortality, especially pneumonia caused by influenza viruses and Streptococcus pneumoniae. However, the synergistic mechanisms remain poorly understood. Therefore, it is necessary to develop a clearer understanding of the molecular basis of the interaction between influenza virus and Streptococcus pneumonia. Here, we developed the BALB/c mouse model and the A549 cell model to investigate inflammation and pyroptotic cell death during co-infection. Co-infection significantly activated the NLRP3 inflammasome and induced pyroptotic cell death, correlated with excess mortality. The E3 ubiquitin ligase NEDD4 interacted with both NLRP3 and GSDMD, the executor of pyroptosis. NEDD4 negatively regulated NLRP3 while positively regulating GSDMD, thereby modulating inflammation and pyroptotic cell death. Our findings suggest that NEDD4 may play a crucial role in regulating the GSDMD-mediated pyroptosis signaling pathway. Targeting NEDD4 represents a promising approach to mitigate excess mortality during influenza pandemics by suppressing synergistic inflammation during co-infection of influenza A virus and Streptococcus pneumoniae.
呼吸道病毒和细菌的合并感染通常会导致过高的死亡率，特别是流感病毒和肺炎链球菌引起的肺炎。然而，协同作用的机制仍知之甚少。因此，有必要更清楚地了解流感病毒和肺炎链球菌相互作用的分子基础。在这里，我们建立了 BALB/c 小鼠模型和 A549 细胞模型，以研究合并感染期间的炎症和细胞焦亡。合并感染显著激活了 NLRP3 炎性小体，并诱导了细胞焦亡死亡，与过高的死亡率相关。E3 泛素连接酶 NEDD4 与 NLRP3 和 GSDMD 相互作用，后者是细胞焦亡的执行者。NEDD4 负向调节 NLRP3，同时正向调节 GSDMD，从而调节炎症和细胞焦亡。我们的研究结果表明，NEDD4 可能在调节 GSDMD 介导的细胞焦亡信号通路中发挥关键作用。靶向 NEDD4 可能是通过抑制流感病毒和肺炎链球菌合并感染时的协同炎症反应来减轻流感大流行期间过高死亡率的一种有前途的方法。
