GP96 Drives Exacerbation of Secondary Bacterial Pneumonia following Influenza A Virus Infection.
GP96 Drives Exacerbation of Secondary Bacterial Pneumonia following Influenza A Virus Infection.
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DOI：
10.1128/mbio.03269-20
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发表时间：
2021-06-29
期刊：
影响因子：
6.4
通讯作者：
Kawabata S
中科院分区：
文献类型：
--
作者：
Sumitomo T;Nakata M;Nagase S;Takahara Y;Honda-Ogawa M;Mori Y;Akamatsu Y;Yamaguchi M;Okamoto S;Kawabata S
甲型流感病毒（IAV）感染使宿主易患继发性细菌性肺炎，这是流感病毒流行期间发病率和死亡率的主要原因。对iav感染的人上皮细胞与肺炎链球菌相互作用的分析表明，感染的细胞在表面异位地表现出内质网伴侣糖蛋白96 （GP96）。重要的是，肺炎球菌对上皮细胞的有效粘附是通过与细胞外GP96和整合素αV的相互作用赋予的，其表面表达由GP96伴侣活性介导。此外，通过化学抑制或基因敲除GP96以及添加RGD肽（一种整合素配体相互作用的抑制剂）来消除粘附性。细胞外GP96与肺炎球菌的直接结合被证明是由肺炎球菌寡肽渗透酶成分介导的。此外，IAV感染诱导calpain和Snail1的激活，它们分别负责宿主连接蛋白的降解和转录抑制，表明细菌跨上皮屏障的易位增加。值得注意的是，用GP96抑制剂治疗iav感染小鼠可增强肺组织对肺炎球菌的清除，并改善肺部病理。综上所述，目前的研究结果表明，病毒-细菌协同作用与疾病进展有关，并为开发专门用于抑制iav感染呼吸道中肺炎球菌定植的新型治疗策略提供了范例。
Influenza A virus (IAV) infection predisposes the host to secondary bacterial pneumonia, known as a major cause of morbidity and mortality during influenza virus epidemics. Analysis of interactions between IAV-infected human epithelial cells and Streptococcus pneumoniae revealed that infected cells ectopically exhibited the endoplasmic reticulum chaperone glycoprotein 96 (GP96) on the surface. Importantly, efficient pneumococcal adherence to epithelial cells was imparted by interactions with extracellular GP96 and integrin αV, with the surface expression mediated by GP96 chaperone activity. Furthermore, abrogation of adherence was gained by chemical inhibition or genetic knockout of GP96 as well as addition of RGD peptide, an inhibitor of integrin-ligand interactions. Direct binding of extracellular GP96 and pneumococci was shown to be mediated by pneumococcal oligopeptide permease components. Additionally, IAV infection induced activation of calpains and Snail1, which are responsible for degradation and transcriptional repression of junctional proteins in the host, respectively, indicating increased bacterial translocation across the epithelial barrier. Notably, treatment of IAV-infected mice with the GP96 inhibitor enhanced pneumococcal clearance from lung tissues and ameliorated lung pathology. Taken together, the present findings indicate a viral-bacterial synergy in relation to disease progression and suggest a paradigm for developing novel therapeutic strategies tailored to inhibit pneumococcal colonization in an IAV-infected respiratory tract.