Targeting host calpain proteases decreases influenza A virus infection
Targeting host calpain proteases decreases influenza A virus infection
复制标题
DOI：
10.1152/ajplung.00314.2015
复制
发表时间：
2016-04-01
影响因子：
4.9
通讯作者：
Si-Tahar, Mustapha
中科院分区：
文献类型：
--
作者：
Blanc, Fany;Furio, Laetitia;Si-Tahar, Mustapha
甲型流感病毒 (IAV) 会引发传染性急性呼吸道疾病。为了开发更有效的严重流感治疗方法，需要更好地了解 IAV 发病机制和宿主免疫反应的分子机制。钙蛋白酶是细胞内蛋白酶，参与多种细胞反应，包括炎症。在这里，我们使用体外和体内方法来研究钙蛋白酶信号在 IAV 发病机制中的作用。发现 IAV 感染的支气管上皮细胞中钙蛋白酶的表达和活性发生改变。通过使用小干扰 RNA (siRNA) 基因沉默、钙蛋白酶的特异性合成抑制剂以及过表达钙蛋白酶抑制剂的小鼠，我们发现钙蛋白酶抑制可抑制 IAV 复制以及 IAV 触发的促炎介质分泌和白细胞浸润。值得注意的是，钙蛋白酶抑制对 IAV 感染具有保护作用，因为它显着降低了不仅受到季节性 H3N2 感染而且还受到高毒力 H5N1 IAV 菌株攻击的小鼠的死亡率。因此，我们的研究表明钙蛋白酶是治疗 IAV 急性肺炎的有希望的治疗靶点。
Influenza A viruses (IAV) trigger contagious acute respiratory diseases. A better understanding of the molecular mechanisms of IAV pathogenesis and host immune responses is required for the development of more efficient treatments of severe influenza. Calpains are intracellular proteases that participate in diverse cellular responses, including inflammation. Here, we used in vitro and in vivo approaches to investigate the role of calpain signaling in IAV pathogenesis. Calpain expression and activity were found altered in IAV-infected bronchial epithelial cells. With the use of small-interfering RNA (siRNA) gene silencing, specific synthetic inhibitors of calpains, and mice overexpressing calpastatin, we found that calpain inhibition dampens IAV replication and IAV-triggered secretion of proinflammatory mediators and leukocyte infiltration. Remarkably, calpain inhibition has a protective impact in IAV infection, since it significantly reduced mortality of mice challenged not only by seasonal H3N2- but also by hypervirulent H5N1 IAV strains. Hence, our study suggests that calpains are promising therapeutic targets for treating IAV acute pneumonia.