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，但患者通常 出现临床胃肠道症状，包括腹痛和腹泻。我们最近发现， 引起COVID-19的严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）感染并 在人小肠上皮细胞（IEC）中复制。然而，SARS的分子机制- CoV-2驱动胃肠道病理学，特别是在有既存疾病的脆弱人群中， 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 与健康或炎症性肠病背景下的IEC、肠道免疫反应和微生物组 （IBD）。我们的初步数据表明，与正常的COVID-19患者相比，IBD患者的 组织蛋白酶L在IEC中的表达，这与较高的病毒载量相关。我们的中心假设是SARS- CoV-2诱导了一种独特的肠道病理学和粘膜免疫反应，这种免疫反应是由宿主因素形成的。 (IBD)管腔因子（分泌物、胆汁盐和微生物组）和治疗剂（美沙拉嗪）。具体而言，使用 健康和IBD衍生的类器官，COVID-19患者粪便样本和K18-hACE 2小鼠，我们的目标是（1）定义 SARS-CoV-2感染正常和IBD上皮的宿主因素和细胞机制，（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） 明确影响肠道SARS-CoV-2感染的环境因素。 凭借在IBD、病毒学和宿主-微生物相互作用方面的广泛和协作专业知识，我们希望 解决机制上有趣的和临床上重要的问题，如“什么是肠道致病性， SARS-CoV-2及其如何受到IBD的影响？"，“SARS-CoV-2/COVID-19与肠道的相互作用是什么？ 炎症和IBD治疗？"，和“肠内容物和IBD诊断/微生物组的影响是什么 肠道SARS-CoV-2？我们期望这种病理学将进一步加深我们对SARS-CoV-2的理解 与上皮细胞和免疫细胞的相互作用，以解释COVID-19 GI症状伴或不伴IBD。我们也 我希望通过本项目获得的新信息将扩大我们对急性胃肠道疾病的认识， COVID-19的病理学和症状，为现有的临床和翻译文献提供了机制背景， 并为深入调查COVID-19创建基础知识和工具集， 未来的致病性和新兴冠状病毒。

Project Summary Although coronavirus disease 2019 (COVID-19) is primarily defined as a respiratory illness, patients often experience clinical gastrointestinal symptoms, including 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 of SARS- CoV-2 driving gastrointestinal pathology, particularly in vulnerable populations with preexisting 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 inflammatory bowel disease (IBD). Our preliminary data suggest that compared to normal COVID-19 patients, those with IBD have higher expression of cathepsin L in IECs, which correlated with 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 (secretions, bile salts, and microbiome), and therapeutics (mesalamine). Specifically, using healthy and IBD-derived organoids, COVID-19 patient fecal samples, and K18-hACE2 mice, 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 IBD, virology, and host-microbial interactions, we expect to address mechanistically interesting and clinically important questions like “What is the intestinal pathogenicity of SARS-CoV-2 and how is it impacted by IBD?”, “What is the interaction of SARS-CoV-2/COVID-19 with intestinal inflammation and IBD therapies?”, and “What is the impact of intestinal contents and IBD diagnosis/microbiome on intestinal SARS-CoV-2?”. We anticipate that this pathology 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 gastrointestinal pathology and symptoms of COVID-19, provide mechanistic context to existing clinical and translational literature, and create a foundational knowledge and tool set for deeper investigations into COVID-19 and potentially pathogenic and emerging coronaviruses of the future.