Mechanisms of Gastrointestinal COVID-19

项目摘要 虽然冠状病毒病2019(新冠肺炎)最初被定义为一种呼吸系统疾病，但患者往往 出现临床胃肠道症状，包括腹痛和腹泻。我们最近发现， 引起新冠肺炎的严重急性呼吸综合征冠状病毒2(SARS-CoV-2)感染和 在人小肠上皮细胞(IECS)中复制。然而，SARS的分子机制-- 驱动胃肠道病理的CoV-2病毒，特别是在有既往疾病的易感人群中仍然存在 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 在健康或炎症性肠病的背景下，IECS、肠道免疫反应和微生物组 (IBD)。我们的初步数据表明，与正常的新冠肺炎患者相比，IBD患者的 组织蛋白酶L在血管内皮细胞中的表达与病毒载量增加有关。我们的中心假设是SARS- CoV-2诱导一种由宿主因素塑造的独特的肠道病理和粘膜免疫反应 肠易激综合征(IBD)、腔因子(分泌物、胆盐和微生物组)和治疗药物(美沙拉明)。具体地说，使用 健康和炎症性肠病衍生的有机类化合物，新冠肺炎患者的粪便样本，以及K18-hACE2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) 确定肠道感染SARS-CoV-2对肠道免疫反应和结肠炎的影响，以及(3) 明确影响SARS-CoV-2肠道感染的环境因素。 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 解决机械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及其受传染性法氏囊病的影响？“，”SARS-CoV-2/新冠肺炎与肠道的相互作用 炎症和IBD治疗？“，以及”肠道内容物和IBD诊断/微生物组有什么影响？“ 肠道SARS-CoV-2？“。我们预计，这一病理将加深我们对SARS-CoV-2的了解 与上皮细胞和免疫细胞的相互作用解释伴有或不伴有IBD的新冠肺炎胃肠道症状。我们也 希望从这个项目中获得的新信息将扩大我们对急性胃肠道疾病的理解 新冠肺炎的病理和症状，为现有的临床和翻译文献提供了机械性的背景， 并为更深入地调查新冠肺炎和潜在的 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.