Duan Fuyu, Guo Liyan, Yang Liuliu, Han Yuling, Thakur Abhimanyu, Nilsson-Payant Benjamin E, Wang Pengfei, Zhang Zhao, Yan Ma Chui, Zhou Xiaoya, Han Teng, Zhang Tuo, Wang Xing, Xu Dong, Duan Xiaohua, Xiang Jenny, Tse Hung-Fat, Liao Can, Luo Weiren, Huang Fang-Ping, Chen Ya-Wen, Evans Todd, Schwartz Robert E, tenOever Benjamin, Ho David D, Chen Shuibing, Na Jie, Lian Qizhou, Chen Huanhuan Joyce
School of Medicine, Tsinghua University.
Prenatal Diagnostic Centre and Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University.
Res Sq. 2020 Sep 15:rs.3.rs-62758. doi: 10.21203/rs.3.rs-62758/v2.
Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies. Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Among the hPSC-derived lung cells, alveolar type II and ciliated cells are the major cell populations expressing the viral receptor ACE2 and co-effector TMPRSS2, and both were highly permissive to viral infection. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 and IL-18, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper-inflammatory response mediated by M1 macrophages.
功能失调的免疫反应对2019冠状病毒病（COVID-19）从轻症发展到包括死亡在内的重症阶段起着关键作用，促炎巨噬细胞是肺部过度炎症的主要介质之一。因此，迫切需要更好地了解严重急性呼吸综合征冠状病毒2（SARS-CoV-2）易感细胞、巨噬细胞和SARS-CoV-2病毒之间的相互作用，从而为新的治疗策略提供重要见解。在这里，我们利用人类多能干细胞（hPSC）的定向分化建立了肺和巨噬细胞共培养系统，并模拟了SARS-CoV-2感染引起的宿主-病原体相互作用和免疫反应。在hPSC来源的肺细胞中，II型肺泡细胞和纤毛细胞是表达病毒受体血管紧张素转换酶2（ACE2）和协同效应器跨膜丝氨酸蛋白酶2（TMPRSS2）的主要细胞群体，两者都对病毒感染高度易感。我们发现，交替极化的巨噬细胞（M2）和经典极化的巨噬细胞（M1）对SARS-CoV-2感染具有相似的抑制作用。然而，只有M1巨噬细胞显著上调包括白细胞介素6（IL-6）和白细胞介素18（IL-18）在内的炎症因子，抑制肺细胞生长并增强其凋亡。使用ACE2阻断抗体抑制病毒进入靶细胞可增强M2巨噬细胞的活性，导致病毒几乎完全清除并保护肺细胞。这些结果提示了一种潜在的治疗策略，即在感染早期通过阻断病毒进入靶细胞同时增强巨噬细胞的抗炎作用，M2巨噬细胞可以清除SARS-CoV-2，同时保护肺细胞并抑制由M1巨噬细胞介导的功能失调的过度炎症反应。
