Mechanisms of Gastrointestinal COVID-19

项目摘要 虽然冠状病毒病2019年(新冠肺炎)主要定义为呼吸系统疾病，但多达50%的 患者会出现临床胃肠道症状，包括恶心、腹痛和腹泻。我们 最近发现严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)，引起 新冠肺炎在人的小肠上皮细胞(IECs)中感染和复制。然而，分子 SARS-CoV-2驱动胃肠道病变的机制及其对粘膜免疫的影响 反应和系统性疾病仍不清楚。 在这项提案中，我们的总体目标是更好地定义SARS-CoV-2相互作用的细胞信号 IECS、肠道免疫反应和健康或发炎肠道环境中的微生物组(即， 炎症性肠病(IBD))。我们的初步数据表明，与正常的新冠肺炎患者相比， 感染前IEC组织蛋白酶L高表达的IBD患者支持较高的病毒载量。 我们的中心假设是SARS-CoV-2诱导了一种独特的肠道病理和粘膜免疫 由宿主因素(IBD)、腔因素(胆盐和微生物组)和治疗方法决定的反应。 具体地说，使用健康的和炎症性肠病衍生的有机物，新冠肺炎患者的粪便样本，SARS-CoV-2变种， 和一个高度易处理和创新的腔内注射小鼠模型，我们的目标是(1)定义宿主因素 以及SARS-CoV-2感染正常上皮和IBD上皮的细胞机制，(2)确定 肠道感染SARS-CoV-2对肠道免疫反应和结肠炎的影响，以及(3)确定 影响SARS-CoV-2肠道感染的环境因素 在肠道生物学、病毒学和粘膜免疫学(包括 IBD)，我们希望解决有关SARS-CoV的机械上有趣和临床上重要的问题- 2肠道感染、免疫反应和肠道病理。我们预计，从 这项研究将进一步了解SARS-CoV-2与上皮细胞和免疫细胞的相互作用 解释患有或不伴有IBD的新冠肺炎胃肠道症状。我们也期待从这个项目中获得新的信息 将扩大我们对COVID-19急慢性胃肠道病理和症状的了解， 提供新的策略来缓解新冠肺炎相关的胃肠道疾病，并创建基础性知识 和工具集，用于深入调查新冠肺炎和可能致病的和新出现的冠状病毒 未来。

Project Summary Although coronavirus disease 2019 (COVID-19) is primarily defined as a respiratory illness, up to 50% of patients experience clinical gastrointestinal symptoms, including nausea, abdominal pain, and diarrhea. We recently found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, infects and replicates in human small bowel intestinal epithelial cells (IECs). However, the molecular mechanisms by which SARS-CoV-2 drives gastrointestinal pathology and how that impacts the mucosal immune responses and systemic diseases remain unclear. In this proposal, our overall objectives are to better define the cellular signaling of SARS-CoV-2 interactions with IECs, enteric immune responses, and microbiome in the context of health or inflamed intestines (i.e., inflammatory bowel disease (IBD)). Our preliminary data suggest that compared to normal COVID-19 patients, those with IBD who have higher expression of cathepsin L in IECs prior to infection, supported higher viral loads. Our central hypothesis is that SARS-CoV-2 induces a distinctive intestinal pathology and mucosal immune response that is shaped by host factors (IBD), luminal factors (bile salts and microbiome), and therapeutics. Specifically, using healthy and IBD-derived organoids, COVID-19 patient fecal samples, SARS-CoV-2 variants, and a highly tractable and innovative intraluminal injection mouse model, we aim to (1) define the host factors and cellular mechanisms involved in SARS-CoV-2 infection of normal and IBD epithelium, (2) determine the impact of intestinal SARS-CoV-2 infection on intestinal immune response and colitis, and (3) define the environmental factors that influence intestinal infection with SARS-CoV-2. With extensive and collaborative expertise in intestinal biology, virology, and mucosal immunology (including IBD), we expect to address mechanistically interesting and clinically important questions regarding SARS-CoV- 2 enteric infection, immune responses, and intestinal pathology. We anticipate that the knowledge derived from this study will further our understanding of SARS-CoV-2 interactions with the epithelial and immune cells to explain COVID-19 GI symptoms with or without IBD. We also expect the new information gained from this project will expand our understanding of acute and chronic gastrointestinal pathology and symptoms of COVID-19, provide novel strategies to mitigate COVID-19 associated GI diseases, and create a foundational knowledge and tool set for deeper investigations into COVID-19 and potentially pathogenic and emerging coronaviruses of the future.