Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip.
Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip.
复制标题
DOI：
10.3389/fphar.2021.718484
复制
发表时间：
2021
影响因子：
5.6
通讯作者：
Ingber DE
中科院分区：
文献类型：
--
作者：
Bein A;Kim S;Goyal G;Cao W;Fadel C;Naziripour A;Sharma S;Swenor B;LoGrande N;Nurani A;Miao VN;Navia AW;Ziegler CGK;Montañes JO;Prabhala P;Kim MS;Prantil-Baun R;Rodas M;Jiang A;O'Sullivan L;Tillya G;Shalek AK;Ingber DE
许多冠状病毒感染的患者，如SARS-CoV-2和NL63，利用ACE2受体感染细胞，出现胃肠道症状和病毒蛋白，但对冠状病毒感染对人体肠道的炎症和病理影响知之甚少。在这里，我们使用了一种由患者器官来源的肠上皮与人血管内皮细胞连接而成的人肠芯片微流控培养装置，以研究宿主细胞和炎症对感染NL63冠状病毒的反应。与作为有机物质或在Transwell插入物中静态培养时相比，当在肠芯片中存在蠕动样机械变形的情况下流动培养时，这些类器官来源的肠上皮细胞的ACE2蛋白水平显著增加。NL63芯片上的肠上皮细胞感染导致内皮细胞炎症，表现为屏障功能丧失，细胞因子产生增加，循环外周血单核细胞(PBMC)募集。用批准的蛋白酶抑制剂药物那法莫司治疗NL63感染的芯片，可以抑制病毒进入，并导致病毒载量和细胞因子分泌减少，而雷米德韦是少数几种批准用于COVID19患者的药物之一，但没有发现有效，它对血管内皮细胞也有毒性。这种肠道感染模型也被用来测试其他被提议用于潜在的抗SARS-CoV-2药物的效果。综上所述，这些数据表明，人体肠道芯片可能是一个有用的人类临床前模型，用于研究冠状病毒相关的病理以及测试潜在的抗病毒或抗炎治疗药物。
Many patients infected with coronaviruses, such as SARS-CoV-2 and NL63 that use ACE2 receptors to infect cells, exhibit gastrointestinal symptoms and viral proteins are found in the human gastrointestinal tract, yet little is known about the inflammatory and pathological effects of coronavirus infection on the human intestine. Here, we used a human intestine-on-a-chip (Intestine Chip) microfluidic culture device lined by patient organoid-derived intestinal epithelium interfaced with human vascular endothelium to study host cellular and inflammatory responses to infection with NL63 coronavirus. These organoid-derived intestinal epithelial cells dramatically increased their ACE2 protein levels when cultured under flow in the presence of peristalsis-like mechanical deformations in the Intestine Chips compared to when cultured statically as organoids or in Transwell inserts. Infection of the intestinal epithelium with NL63 on-chip led to inflammation of the endothelium as demonstrated by loss of barrier function, increased cytokine production, and recruitment of circulating peripheral blood mononuclear cells (PBMCs). Treatment of NL63 infected chips with the approved protease inhibitor drug, nafamostat, inhibited viral entry and resulted in a reduction in both viral load and cytokine secretion, whereas remdesivir, one of the few drugs approved for COVID19 patients, was not found to be effective and it also was toxic to the endothelium. This model of intestinal infection was also used to test the effects of other drugs that have been proposed for potential repurposing against SARS-CoV-2. Taken together, these data suggest that the human Intestine Chip might be useful as a human preclinical model for studying coronavirus related pathology as well as for testing of potential anti-viral or anti-inflammatory therapeutics.
登录
查看更多内容
影响因子：
29.4
作者：
Jiao L;Li H;Xu J;Yang M;Ma C;Li J;Zhao S;Wang H;Yang Y;Yu W;Wang J;Yang J;Long H;Gao J;Ding K;Wu D;Kuang D;Zhao Y;Liu J;Lu S;Liu H;Peng X
通讯作者：
Peng X
影响因子：
56.9
作者：
Lamers, Mart M.;Beumer, Joep;Clevers, Hans
通讯作者：
Clevers, Hans
影响因子：
5.4
作者：
Milewska, Aleksandra;Nowak, Paulina;Pyrc, Krzysztof
通讯作者：
Pyrc, Krzysztof
95例SARS-CoV-2胃肠道症状
影响因子：
24.5
作者：
Lin, Lu;Jiang, Xiayang;Shan, Hong
通讯作者：
Shan, Hong
影响因子：
32.4
作者：
Hughes TK;Wadsworth MH 2nd;Gierahn TM;Do T;Weiss D;Andrade PR;Ma F;de Andrade Silva BJ;Shao S;Tsoi LC;Ordovas-Montanes J;Gudjonsson JE;Modlin RL;Love JC;Shalek AK
通讯作者：
Shalek AK