PDF(Pubmed)
Abstract：
Influenza A virus (IAV) infection often leads to influenza-associated fatalities, frequently compounded by subsequent bacterial infections, particularly Gram-negative bacterial co-infections. Lipopolysaccharide (LPS), a primary virulence factor in Gram-negative bacteria, plays a crucial role in influenza-bacterial co-infections. However, the precise pathogenic mechanisms underlying the synergistic effects of viral-bacterial co-infections remain elusive, posing significant challenges for disease management. In our study, we administered a combination of IAV and LPS to mice and examined associated parameters, including the lung function, lung index, wet/dry ratio, serum inflammatory cytokines, Nedd4L expression in lung tissue, and mRNA levels of inflammatory cytokines. Co-infection with IAV and LPS exacerbated lung tissue inflammation and amplified M1 macrophage expression in lung tissue. Additionally, we stimulated macrophages with IAV and LPS in vitro, assessing the inflammatory cytokine content in the cell supernatant and cytokine mRNA expression within the cells. This combined stimulation intensified the inflammatory response in macrophages and upregulated Nedd4L protein and mRNA expression. Subsequently, we used siRNA to knockdown Nedd4L in macrophages, revealing that suppression of Nedd4L expression alleviated the inflammatory response triggered by concurrent IAV and LPS stimulation. Collectively, these results highlight the pivotal role of Nedd4L in mediating the exacerbated inflammatory responses observed in IAV and LPS co-infections.
摘要：
甲型流感病毒（IAV）感染通常会导致与流感相关的死亡。经常因随后的细菌感染而加剧，特别是革兰氏阴性细菌共感染。脂多糖（LPS），革兰氏阴性菌的主要毒力因子，在流感-细菌共感染中起着至关重要的作用。然而,病毒-细菌共感染的协同作用的精确致病机制仍然难以捉摸，对疾病管理构成重大挑战。在我们的研究中,我们给小鼠服用了IAV和LPS的组合，并检查了相关参数，包括肺功能,肺指数,湿/干比，血清炎性细胞因子，Nedd4L在肺组织中的表达，和炎性细胞因子的mRNA水平。IAV和LPS共感染加剧了肺组织炎症，并放大了肺组织中M1巨噬细胞的表达。此外,我们在体外用IAV和LPS刺激巨噬细胞，评估细胞上清液中的炎性细胞因子含量和细胞内的细胞因子mRNA表达。这种组合刺激增强了巨噬细胞的炎症反应，并上调了Nedd4L蛋白和mRNA的表达。随后，我们用siRNA敲除巨噬细胞中的Nedd4L,显示抑制Nedd4L表达减轻了由IAV和LPS同时刺激引发的炎症反应。总的来说，这些结果强调了Nedd4L在介导IAV和LPS共感染中观察到的加剧的炎症反应中的关键作用.
