SARS-CoV-2 infection and replication in human gastric organoids. 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）通常以呼吸道疾病为主要临床表现，但多项临床报告均提及胃肠道（GI，gastrointestinal）症状。该现象在儿童群体中尤为突出：其胃肠道症状发生率较高，且病毒脱落（viral shedding）的持续时间长于呼吸道系统的病毒清除周期。上述观察结果引发了一个核心问题：该病毒是否可在胃内进行复制？
本研究首次从胎儿、儿童及成人的胃活检组织中成功构建胃类器官（gastric organoids），并证实其可作为严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）感染的体外（in vitro）模型。为提升感染效率，我们对类器官进行了极性反转修饰，获得反转极性胃类器官（RP-GOs，reversed polarity gastric organoids）。
儿童来源的反转极性胃类器官对SARS-CoV-2感染完全易感，而胎儿与成人来源的类器官的病毒复制水平显著降低。转录组分析（transcriptomic analysis）显示，宿主仅产生中等强度的天然抗病毒应答，且未检测到干扰素家族相关的差异表达基因。
综上，本研究证实该病毒可高效感染胃上皮细胞，提示胃部可能在严重急性呼吸综合征冠状病毒2型的粪口传播中发挥主动作用。
实验整体设计：以感染复数（MOI，multiplicity of infection）为1的SARS-CoV-2病毒感染胎儿、儿童及成人来源的胃组织类器官，并设置配对阴性对照组，随后开展转录组分析。