NEDD4 Regulated Pyroptosis Occurred from Co-infection between Influenza A Virus and Streptococcus pneumoniae
Jiangzhou You1, Linlin Zhou1, Xudong San2
1Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610000, People's Republic of China.
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.
Insights
Co-infection with influenza virus and Streptococcus pneumoniae causes excess mortality by activating pyroptosis. The E3 ligase NEDD4 regulates this cell death pathway, offering a potential therapeutic target to reduce deaths during influenza pandemics.
Area of Science:
- Immunology
- Molecular Biology
- Pathology
Background:
- Bacterial and viral respiratory co-infections, particularly with influenza viruses and Streptococcus pneumoniae, contribute significantly to excess mortality.
- The molecular mechanisms underlying the synergistic interactions and increased severity during these co-infections remain largely unknown.
Purpose of the Study:
- To elucidate the molecular mechanisms of inflammation and pyroptotic cell death during influenza virus and Streptococcus pneumoniae co-infection.
- To investigate the role of the E3 ubiquitin ligase NEDD4 in regulating these processes.
Main Methods:
- Utilized BALB/c mouse and A549 cell models to simulate co-infection conditions.
- Investigated the activation of the NLRP3 inflammasome and pyroptotic cell death pathways.
- Examined the interaction of NEDD4 with NLRP3 and GSDMD (Gasdermin D).
Main Results:
- Co-infection significantly activated the NLRP3 inflammasome, leading to pyroptotic cell death and increased mortality.
- NEDD4 was found to interact with both NLRP3 and GSDMD.
- NEDD4 negatively regulated NLRP3 activity while positively regulating GSDMD, thereby modulating inflammation and pyroptosis.
Conclusions:
- NEDD4 plays a critical role in regulating GSDMD-mediated pyroptosis during respiratory co-infections.
- Targeting NEDD4 presents a potential therapeutic strategy to mitigate excess mortality associated with influenza pandemics and secondary bacterial pneumonia.
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