SARS-CoV-2 infection and replication in human gastric organoids

COVID-19 typically manifests as a respiratory illness but several clinical reports described gastrointestinal (GI) symptoms. This is particularly true in children, whom GI symptoms are frequent and viral shedding outlasts viral clearance from the respiratory system. These observations raise the question of whether the virus can replicate within the stomach. Here we show the novel derivation of gastric organoids from fetal, pediatric and adult biopsies and prove their value as in vitro models for SARS-CoV-2 infection. To facilitate infection, we induced a reversed polarity in our organoids (RP-GOs). The pediatric RP-GOs are fully susceptible to infection with SARS-CoV-2, while the viral replication is significantly lower in organoids of fetal and adult origin. Transcriptomic analysis shows a moderate innate antiviral response and the lack of differentially expressed genes belonging to the interferon family. Collectively, we show how the virus can efficiently infect gastric epithelium, suggesting that the stomach might have an active role in fecal-oral SARS-CoV-2 transmission. Overall design: Transcriptomic analysis of organoids derived from fetal, pediatric and adult gastric samples infected by SARS-CoV-2 virus at MOI 1, and paired negative controls.

新型冠状病毒肺炎（COVID-19）通常表现为呼吸道疾病，但多项临床研究报道了胃肠道（gastrointestinal, GI）相关症状。这一点在儿童群体中尤为显著：其胃肠道症状频发，且病毒排毒（viral shedding）时长超过呼吸系统的病毒清除时长。上述观察结果提出了一个核心疑问：该病毒是否可在胃内进行复制。
本研究首次建立了从胎儿、儿童及成人活检组织中获取胃类器官（gastric organoids）的方法，并证实其可作为严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染的体外模型。为优化感染实验条件，我们将类器官诱导为反向极性表型（reversed polarity organoids, RP-GOs）。实验结果显示，儿童来源的RP-GOs对SARS-CoV-2感染完全易感，而胎儿及成人来源的类器官的病毒复制水平则显著降低。转录组学分析表明，样本呈现适度的天然抗病毒应答，且未检测到干扰素家族的差异表达基因。
综上，本研究证实该病毒可高效感染胃上皮细胞，提示胃可能在SARS-CoV-2的粪口传播中发挥活跃作用。
实验整体设计：对感染复数（multiplicity of infection, MOI）为1的SARS-CoV-2感染的胎儿、儿童及成人胃组织来源类器官，及其配对阴性对照样本开展转录组学分析。