Mechanisms of Gastrointestinal COVID-19

项目摘要 尽管2019年冠状病毒病（COVID-19）主要被定义为呼吸道疾病，但高达50%的 患者出现临床胃肠道症状，包括恶心、腹痛和腹泻。我们 最近发现，严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）， COVID-19在人类小肠上皮细胞（IEC）中感染和复制。然而，分子 SARS-CoV-2驱动胃肠道病理学的机制及其如何影响粘膜免疫 反应和全身性疾病仍不清楚。 在这个提议中，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传导 在健康或发炎的肠的情况下（即， 炎症性肠病（IBD））。我们的初步数据表明，与正常的COVID-19患者相比， 那些感染前在IEC中组织蛋白酶L表达较高的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反应， 由宿主因子（IBD）、管腔因子（胆汁盐和微生物组）和治疗剂形成的反应。 具体而言，使用健康和IBD衍生的类器官、COVID-19患者粪便样本、SARS-CoV-2变体， 和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感染正常和IBD上皮细胞的细胞机制，（2）确定 肠道SARS-CoV-2感染对肠道免疫应答和结肠炎的影响，以及（3）确定 环境因素影响肠道感染SARS-CoV-2。 在肠道生物学、病毒学和粘膜免疫学（包括 IBD），我们期望解决有关SARS-CoV的机制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，知识来源于 这项研究将进一步加深我们对SARS-CoV-2与上皮细胞和免疫细胞相互作用的理解， 解释COVID-19 GI症状伴或不伴IBD。我们也期待着从这个项目中获得新的信息 将扩大我们对急性和慢性胃肠道病理学以及COVID-19症状的理解， 提供新的策略，以减轻COVID-19相关的胃肠道疾病，并创造一个基础知识 和工具集，用于深入调查COVID-19和潜在致病性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.