A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics.
A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics.
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DOI：
10.1038/s41551-021-00718-9
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发表时间：
2021-08
影响因子：
28.1
通讯作者：
Ingber DE
中科院分区：
文献类型：
--
作者：
Si L;Bai H;Rodas M;Cao W;Oh CY;Jiang A;Moller R;Hoagland D;Oishi K;Horiuchi S;Uhl S;Blanco-Melo D;Albrecht RA;Liu WC;Jordan T;Nilsson-Payant BE;Golynker I;Frere J;Logue J;Haupt R;McGrath M;Weston S;Zhang T;Plebani R;Soong M;Nurani A;Kim SM;Zhu DY;Benam KH;Goyal G;Gilpin SE;Prantil-Baun R;Gygi SP;Powers RK;Carlson KE;Frieman M;tenOever BR;Ingber DE
抗病毒药物的快速再利用在大流行期间尤其紧迫。然而，用于评估候选药物的快速测定通常涉及在组织和器官水平上不再现人类生理学的体外筛选和细胞系。在这里，我们表明，一个微流控支气管气道芯片内衬高度分化的人支气管气道上皮细胞和肺内皮细胞可以模拟病毒感染，应变依赖的毒力，细胞因子的产生，和循环免疫细胞的招聘。在感染甲型流感病毒的气道芯片中，萘莫司他与奥司他韦联合给药使奥司他韦的治疗时间窗增加了一倍。在感染了假型SARS-CoV-2（严重急性呼吸道综合征冠状病毒2型）的芯片中，临床相关剂量的抗疟药阿莫地喹抑制了感染，但临床剂量的羟氯喹和其他抗病毒药物抑制了假型SARS-CoV-2在静态条件下进入细胞系。我们还表明，阿莫地喹在用天然SARS-CoV-2攻击的仓鼠中显示出实质性的预防和治疗活性。芯片上的人类气道可以加速识别具有再利用潜力的治疗剂和药物。由人支气管气道上皮和肺内皮内衬的微流体支气管气道芯片可用于快速鉴定具有再利用潜力的抗病毒治疗剂和药物。
The rapid repurposing of antivirals is particularly pressing during pandemics. However, rapid assays for assessing candidate drugs typically involve in vitro screens and cell lines that do not recapitulate human physiology at the tissue and organ levels. Here, we show that a microfluidic bronchial-airway-on-a-chip lined by highly differentiated human bronchial-airway epithelium and pulmonary endothelium can model viral infection, strain-dependent virulence, cytokine production, and the recruitment of circulating immune cells. In airway chips infected with influenza A, the co-administration of nafamostat with oseltamivir doubled the treatment-time window for oseltamivir. In chips infected with pseudotyped SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), clinically relevant doses of the antimalarial drug amodiaquine inhibited infection, but clinical doses of hydroxychloroquine and other antiviral drugs that inhibit the entry of pseudotyped SARS-CoV-2 in cell lines under static conditions did not. We also show that amodiaquine showed substantial prophylactic and therapeutic activities in hamsters challenged with native SARS-CoV-2. The human airway-on-a-chip may accelerate the identification of therapeutics and prophylactics with repurposing potential. A microfluidic bronchial-airway-on-a-chip lined by human bronchial-airway epithelium and pulmonary endothelium can be used to rapidly identify antiviral therapeutics and prophylactics with repurposing potential.
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影响因子：
158.5
作者：
Boulware, David R.;Pullen, Matthew F.;Hullsiek, Kathy H.
通讯作者：
Hullsiek, Kathy H.
影响因子：
2.7
作者：
Hattermann, K;Müller, MA;Niedrig, M
通讯作者：
Niedrig, M
影响因子：
5
作者：
Chan, Renee W. Y.;Chan, Michael C. W.;Nicholls, John M.;Peiris, J. S. Malik
通讯作者：
Peiris, J. S. Malik
影响因子：
76.2
作者：
Hui, Kenrie P. Y.;Ching, Rachel H. H.;Chan, Michael C. W.
通讯作者：
Chan, Michael C. W.
影响因子：
32.4
作者：
Hoagland DA;Møller R;Uhl SA;Oishi K;Frere J;Golynker I;Horiuchi S;Panis M;Blanco-Melo D;Sachs D;Arkun K;Lim JK;tenOever BR
通讯作者：
tenOever BR