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NEDD4 Regulated Pyroptosis Occurred from Co-infection between Influenza A Virus and Streptococcus pneumoniae

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Abstract

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.

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Data availability

The datasets generated or analyzed during this study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was financially supported by the open foundation of the State Key Laboratory of Oral Diseases (Grant no. SKLOD2015OF08). We thank Prof. Yan Li and Dr. Wei Wei for the manuscript revision from West China Hospital of Stomatology, Sichuan University. We thank Prof. Tao Luo from the Department of Pathogenic Biology of the West China School of Basic Medical Sciences & Forensic Medicine of Sichuan University. We thank Prof. Qiang Fu and Prof. **ghu Zhang from the Public Platform of the West China School of Basic Medical Sciences & Forensic Medicine of Sichuan University. We thank the Department of Pathogenic Biology of the West China School of Basic Medical Sciences & Forensic Medicine of Sichuan University, and the Public Platform of the West China School of Basic Medical Sciences & Forensic Medicine of Sichuan University for providing core facility assistance. At the same time, we thank Dr. Zhen Qin from the Department of Pathogenic Biology of the West China School of Basic Medical Sciences & Forensic Medicine of Sichuan University, Prof. Zairong Zhang from the Department of Pathogenic Biology of the West China School of Basic Medical Sciences & Forensic Medicine of Sichuan University, Dr. Laibin Ren from the Department of Pathophysiology, and Prof. Yang Qin and Prof. **ufeng Gao from the Department of Biochemistry for their technical assistance.

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  1. Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610000, People’s Republic of China

    Jiangzhou You, Linlin Zhou, Mingyuan Li & Baoning Wang

  2. Reproductive & Women-Children Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, People’s Republic of China

    Xudong San

  3. Department of Biochemistry, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610000, People’s Republic of China

    Hailing Li

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  1. Jiangzhou You
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Correspondence to Mingyuan Li or Baoning Wang.

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The animal study was reviewed and approved by the Medical Ethics Committee of Sichuan University (WCHSIRB-D-2022–624).

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You, J., Zhou, L., San, X. et al. NEDD4 Regulated Pyroptosis Occurred from Co-infection between Influenza A Virus and Streptococcus pneumoniae. J Microbiol. 61, 777–789 (2023). https://doi.org/10.1007/s12275-023-00076-y

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