Human early syncytiotrophoblasts are highly susceptible to SARS-CoV-2 infection

• Published in: Cell reports. Medicine 2022-12, Vol.3 (12), p.100849-100849, Article 100849
• Main Authors: Ruan, Degong, Ye, Zi-Wei, Yuan, Shuofeng, Li, Zhuoxuan, Zhang, Weiyu, Ong, Chon Phin, Tang, Kaiming, Ka Ki Tam, Timothy Theodore, Guo, Jilong, Xuan, Yiyi, Huang, Yunying, Zhang, Qingqing, Lee, Cheuk-Lun, Lu, Liming, Chiu, Philip C.N., Yeung, William S.B., Liu, Fang, Jin, Dong-Yan, Liu, Pentao
• Format: Article
• Language: English
• Subjects: Antiviral Agents - pharmacology; COVID-19; EPSC; expanded potential stem cell; Female; human trophoblast; Humans; Peptidyl-Dipeptidase A - genetics; Placenta; Pregnancy; Pregnancy Complications, Infectious; SARS-CoV-2; trophoblast organoid; Trophoblasts
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2022.100849

Direct in vivo investigation of human placenta trophoblast’s susceptibility to SARS-CoV-2 is challenging. Here we report that human trophoblast stem cells (hTSCs) and their derivatives are susceptible to SARS-CoV-2 infection, which reveals heterogeneity in hTSC cultures. Early syncytiotrophoblasts (eSTBs) generated from hTSCs have enriched transcriptomic features of peri-implantation trophoblasts, express high levels of angiotensin-converting enzyme 2 (ACE2), and are productively infected by SARS-CoV-2 and its Delta and Omicron variants to produce virions. Antiviral drugs suppress SARS-CoV-2 replication in eSTBs and antagonize the virus-induced blockage of STB maturation. Although less susceptible to SARS-CoV-2 infection, trophoblast organoids originating from hTSCs show detectable viral replication reminiscent of the uncommon placental infection. These findings implicate possible risk of COVID-19 infection in peri-implantation embryos, which may go unnoticed. Stem cell-derived human trophoblasts such as eSTBs can potentially provide unlimited amounts of normal and genome-edited cells and facilitate coronavirus research and antiviral discovery. [Display omitted] •SARS-CoV-2 infects human trophoblast stem cells (hTSCs) and their derivatives•ACE2+ early syncytiotrophoblasts (eSTBs) are susceptible to SARS-CoV-2 and MERS-CoV•eSTB virion production is comparable to that of Vero cells and eliminated by antivirals•Inefficient infection of trophoblast organoids models rare placental infection Ruan et al. utilize human expanded potential stem cells (hEPSCs) to demonstrate the susceptibility of ACE2+ early syncytiotrophoblasts to SARS-CoV-2 variants. Productive viral infection blocks syncytiotrophoblast maturation, which is rescued by antivirals. Trophoblast organoids are inefficiently infected, reflecting uncommon placental infection in vivo.