Streptococcus pneumoniae co-infection post-influenza is a major cause of mortality characterized by uncontrolled bacteria burden and excessive immune response during influenza pandemics. Interleukin (IL)-4 is a canonical type II immune cytokine known for its wide range of biological activities on different cell types. It displays protective roles in numerous infectious diseases and immune-related diseases, but its role in influenza and S. pneumoniae (influenza/S. pneumoniae) co-infected pneumonia has not been reported. In our study, we used C57BL/6 wild-type (WT) and IL-4-deficient (IL-4^−/−) mice to establish co-infection model with S. pneumoniae after influenza virus infection. Co-infected IL-4^−/− mice showed increased mortality and weight loss compared with WT mice. IL-4 deficiency led to increased bacterial loads in lungs without altering influenza virus replication, suggesting a role of IL-4 in decreasing post-influenza susceptibility to S. pneumoniae co-infection. Loss of IL-4 also resulted in aggravated lung damage together with massive proinflammatory cytokine production and immune cell infiltration during co-infection. Administration of recombinant IL-4 rescued the survival and weight loss of IL-4^−/− mice in lethal co-infection. Additionally, IL-4 deficiency led to more immune cell death in co-infection. Gasdermin D (GSDMD) during co-infection was induced in IL-4^−/− mice that subsequently activated cell pyroptosis. Treatment of recombinant IL-4 or inhibition of GSDMD activity by disulfiram decreased immune cell death and bacterial loads in lungs of IL-4^−/− co-infected mice. These results suggest that IL-4 decreases post-influenza susceptibility to S. pneumoniae co-infection via suppressing GSDMD-induced pyroptosis. Collectively, this study demonstrates the protective role of IL-4 in influenza/S. pneumoniae co-infected pneumonia.

中文翻译：

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白细胞介素4保护小鼠免受致命流感和肺炎链球菌共同感染的肺炎

流感后肺炎链球菌合并感染是导致死亡的主要原因，其特征是在流感大流行期间不受控制的细菌负担和过度的免疫反应。白细胞介素 (IL)-4 是一种典型的 II 型免疫细胞因子，以其对不同细胞类型的广泛生物活性而闻名。它在许多传染病和免疫相关疾病中表现出保护作用，但在流感和S . 肺炎链球菌（流感/肺炎链球菌）合并感染的肺炎尚未见报道。在我们的研究中，我们使用 C57BL/6 野生型 (WT) 和 IL-4 缺陷型 (IL-4 ^-/- ) 小鼠与S建立共感染模型。肺炎链球菌流感病毒感染后。与 WT 小鼠相比，共感染的 IL-4 ^-/-小鼠表现出更高的死亡率和体重减轻。IL-4 缺乏导致肺部细菌负荷增加而不改变流感病毒复制，这表明 IL-4 在降低流感后对S的易感性中的作用。肺炎合并感染。IL-4 的缺失还导致肺损伤加重，同时在共感染期间产生大量促炎细胞因子和免疫细胞浸润。^{重组 IL-4 的施用挽救了 IL-4 -/-}小鼠在致死性共感染中的存活和体重减轻。此外，IL-4 缺乏导致更多的免疫细胞在共同感染中死亡。共感染期间的 Gasdermin D (GSDMD) 在 IL-4 中被诱导^-/-随后激活细胞焦亡的小鼠。用双硫仑治疗重组 IL-4 或抑制 GSDMD 活性可减少 IL-4 ^-/-共感染小鼠肺中的免疫细胞死亡和细菌负荷。这些结果表明，IL-4 降低了流感后对链球菌的易感性。通过抑制 GSDMD 诱导的细胞焦亡的肺炎合并感染。总的来说，这项研究证明了 IL-4 在流感/沙门氏菌中的保护作用。肺炎链球菌合并感染的肺炎。