tetano
Editor, Senior Moderator
Cell Death Discov
. 2026 Apr 2.
doi: 10.1038/s41420-026-03031-z. Online ahead of print.
Excessive pyroptosis mediates the exacerbation of pneumonia caused by low-lethality influenza virus and secondary MRSA co-infection
Zi-Chen Tian[SUP] #[/SUP][SUP] 1 [/SUP], Yang Liu[SUP] #[/SUP][SUP] 1 [/SUP], Yi-Jun Niu[SUP] 1 [/SUP], Xin Ai[SUP] 1 [/SUP], Su-Ya Lao[SUP] 1 [/SUP], Wei-Ming Xu[SUP] 1 [/SUP], Xiao-Tong Lin[SUP] 1 [/SUP], Cheng-Jie Xia[SUP] 1 [/SUP], Zhi-Xuan Cai[SUP] 1 [/SUP], Hai-Yan Zhu[SUP] 1 [/SUP], Xun-Long Shi[SUP] 2 [/SUP]
Affiliations
Co-infection with influenza A virus (IAV) and methicillin-resistant Staphylococcus aureus (MRSA) often causes severe pneumonia clinically; however, the role of innate immunity in this setting remains poorly understood. In our study, we established a murine co-infection model using low-lethality IAV and MRSA. Compared with single IAV or MRSA infection, co-infection with relatively low-lethality IAV and MRSA resulted in more severe pneumonia. Transcriptomic analysis indicated marked upregulation of genes involved in the pyroptotic signaling pathway. Consistently, flow cytometry and immunofluorescence analyses revealed caspase-1 activation and colocalization of gasdermin D (GSDMD) with macrophages in the lung. The RAW264.7 macrophage cell line was used for in vitro validation. Co-infection significantly enhanced the cleavage of caspase-1 and GSDMD in RAW264.7 cells. Furthermore, disulfiram, a pyroptosis inhibitor, was incorporated into the antiviral and antibacterial combination treatment. Although combined oseltamivir and linezolid treatment failed to fully alleviate lung injury, the inclusion of disulfiram, a GSDMD pore formation inhibitor, significantly ameliorated pneumonia symptoms and reduced inflammatory responses. Collectively, our findings highlight that macrophage pyroptosis contributes to the exacerbation of pneumonia induced by IAV and secondary MRSA co-infection. Inhibition of GSDMD-mediated pyroptosis may represent a viable therapeutic approach to alleviate disease severity and improve outcomes in lethal co-infection.
. 2026 Apr 2.
doi: 10.1038/s41420-026-03031-z. Online ahead of print.
Excessive pyroptosis mediates the exacerbation of pneumonia caused by low-lethality influenza virus and secondary MRSA co-infection
Zi-Chen Tian[SUP] #[/SUP][SUP] 1 [/SUP], Yang Liu[SUP] #[/SUP][SUP] 1 [/SUP], Yi-Jun Niu[SUP] 1 [/SUP], Xin Ai[SUP] 1 [/SUP], Su-Ya Lao[SUP] 1 [/SUP], Wei-Ming Xu[SUP] 1 [/SUP], Xiao-Tong Lin[SUP] 1 [/SUP], Cheng-Jie Xia[SUP] 1 [/SUP], Zhi-Xuan Cai[SUP] 1 [/SUP], Hai-Yan Zhu[SUP] 1 [/SUP], Xun-Long Shi[SUP] 2 [/SUP]
Affiliations
- PMID: 41927528
- DOI: 10.1038/s41420-026-03031-z
Co-infection with influenza A virus (IAV) and methicillin-resistant Staphylococcus aureus (MRSA) often causes severe pneumonia clinically; however, the role of innate immunity in this setting remains poorly understood. In our study, we established a murine co-infection model using low-lethality IAV and MRSA. Compared with single IAV or MRSA infection, co-infection with relatively low-lethality IAV and MRSA resulted in more severe pneumonia. Transcriptomic analysis indicated marked upregulation of genes involved in the pyroptotic signaling pathway. Consistently, flow cytometry and immunofluorescence analyses revealed caspase-1 activation and colocalization of gasdermin D (GSDMD) with macrophages in the lung. The RAW264.7 macrophage cell line was used for in vitro validation. Co-infection significantly enhanced the cleavage of caspase-1 and GSDMD in RAW264.7 cells. Furthermore, disulfiram, a pyroptosis inhibitor, was incorporated into the antiviral and antibacterial combination treatment. Although combined oseltamivir and linezolid treatment failed to fully alleviate lung injury, the inclusion of disulfiram, a GSDMD pore formation inhibitor, significantly ameliorated pneumonia symptoms and reduced inflammatory responses. Collectively, our findings highlight that macrophage pyroptosis contributes to the exacerbation of pneumonia induced by IAV and secondary MRSA co-infection. Inhibition of GSDMD-mediated pyroptosis may represent a viable therapeutic approach to alleviate disease severity and improve outcomes in lethal co-infection.