Antiviral drug screening by assessing epithelial functions and innate immune responses in human 3D airway epithelium model
Antiviral drug screening by assessing epithelial functions and innate immune responses in human 3D airway epithelium model
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DOI：
10.1016/j.antiviral.2018.06.007
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发表时间：
2018-08-01
影响因子：
7.6
通讯作者：
Constant, Samuel
中科院分区：
文献类型：
--
作者：
Boda, Bernadett;Benaoudia, Sacha;Constant, Samuel
呼吸道病毒感染导致轻微到严重的疾病，如普通感冒、毛细支气管炎和肺炎，并与社会的沉重负担有关。为了测试缩短、减轻疾病的新分子或开发新的治疗方法，相关的人体体外模型是强制性的。MucilAir“是一种人体标准化的气液界面3D呼吸道上皮细胞培养物，在体外拥有与体内情况类似的对抗入侵者的特定机制，如粘液产生、粘液纤毛清除和防御分子的分泌。这项研究的目的是测试这种模型对于抗病毒药物的发现和验证的相关性。在没有或存在参考抗病毒药物的情况下，完全分化的3D鼻黏膜上皮细胞接种微小核糖核酸病毒、冠状病毒和甲型流感病毒。结果表明，鲁宾曲韦以剂量依赖的方式有效地抑制呼吸道小核糖核酸病毒的复制，并防止粘液纤毛清除的损害。同样，奥司他韦以剂量依赖的方式减少甲型流感病毒的复制，并防止上皮屏障功能的损害和细胞毒性，直到感染4天。此外，我们还发现，鼻病毒B14、C15和甲型H1N1流感病毒以不同的时间段诱导13种防御素2和放线菌素的释放显著增加。这些结果表明，大量的上皮功能在病毒感染后被修改，并验证了MucilAir作为临床前抗病毒药物测试的相关工具。
Respiratory viral infections cause mild to severe diseases, such as common cold, bronchiolitis and pneumonia and are associated with substantial burden for society. To test new molecules for shortening, alleviating the diseases or to develop new therapies, relevant human in vitro models are mandatory. MucilAir", a human standardized air-liquid interface 3D airway epithelial culture holds in vitro specific mechanisms to counter invaders comparable to the in vivo situation, such as mucus production, mucociliary clearance, and secretion of defensive molecules. The objective of this study was to test the relevance of such a model for the discovery and validation of antiviral drugs. Fully differentiated 3D nasal epithelium cultures were inoculated with picornaviruses, a coronavirus and influenza A viruses in the absence or in the presence of reference antiviral drugs. Results showed that, rupintrivir efficiently inhibits the replication of respiratory picornaviruses in a dose dependent manner and prevents the impairment of the mucociliary clearance. Similarly, oseltamivir reduced the replication of influenza A viruses in a dose dependent manner and prevented the impairment of the epithelial barrier function and cytotoxicity until 4 days of infection. In addition we found that Rhinovirus B14, C15 and influenza A(H1N1) induce significant increase of 13 Defensins 2 and Cathelicidin release with different time course. These results reveal that a large panel of epithelial functions is modified upon viral infection and validate MucilAir" as a pertinent tool for pre-clinical antiviral drug testing.