Mechanisms of Gastrointestinal COVID-19

胃肠道 COVID-19 的机制

• 批准号: 10665643
• 负责人: MATTHEW AARON CIORBA
• 金额: $ 70.58万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665643
• 关键词: 16S ribosomal RNA sequencing; 2019-nCoV; ACE2; Abdominal Pain; Acute; Address; Affect; Biology; COVID-19; COVID-19 patient; COVID-19 severity; COVID-19 treatment; COVID-19 vaccination; Cathepsin L; Cell Death; Cells; Chronic; Clinical; Colitis; Colon; Coronavirus; Crohn' s disease; Data; Diarrhea; Disease; Endosomes; Enteral; Enterocytes; Environmental Risk Factor; Epithelial Cells; Epithelium; Etiology; Feces; Functional disorder; Future; Gastrointestinal Diseases; Gastrointestinal Physiology; Gastrointestinal tract structure; Genetic; Genotype; Health; Homeostasis; Household; Human; Immune; Immune response; Immunology; Impairment; Infection; Inflammation; Inflammatory Bowel Diseases; Injections; Integration Host Factors; Intervention; Intestinal Diseases; Intestines; Investigation; Knowledge; Liquid substance; Lower Gastrointestinal Tract; Modeling; Molecular; Mucosal Immune Responses; Mucosal Immune System; Mucositis; Mucous Membrane; Mus; Nausea; Observational Study; Organ; Organoids; Outcome; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Populations at Risk; Reporter; Respiratory System; Role; SARS-CoV-2 B.1.617.2; SARS-CoV-2 P.1; SARS-CoV-2 infection; SARS-CoV-2 variant; Sampling; Severity of illness; Shapes; Signal Transduction; Site; Small Intestines; Specimen; Symptoms; Systemic disease; Testing; Therapeutic; Therapeutic immunosuppression; Transgenic Mice; Tropism; Viral Load result; Viral reservoir; Virus; Vomiting; acute infection; bile salts; biobank; coronavirus disease; diarrheal disease; differential expression; enteric infection; experience; gastrointestinal; gastrointestinal infection; gastrointestinal symptom; gut dysbiosis; gut inflammation; gut microbiome; infection rate; inhibitor; innovation; intestinal epithelium; microbiome; microbiota; mouse model; novel; novel coronavirus; novel strategies; pharmacologic; respiratory; socioeconomics; stool sample; tool; virology; virome; virus resource

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.

项目摘要 尽管2019年冠状病毒病（COVID-19）主要定义为呼吸道疾病，但多达50％ 患者患有临床胃肠道症状，包括恶心，腹痛和腹泻。我们 最近发现，严重的急性呼吸道综合征冠状病毒2（SARS-COV-2），导致的病毒 COVID-19，在人类小肠肠上皮细胞（IEC）中感染和复制。但是，分子 SARS-COV-2驱动胃肠道病理以及如何影响粘膜免疫的机制 反应和全身性疾病尚不清楚。 在此提案中，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传导 在健康或发炎的肠道背景下，具有IEC，肠性免疫反应和微生物组（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 在感染前IEC中，IBD在IEC中具有较高表达的IBD的人支持较高的病毒载荷。 我们的中心假设是SARS-COV-2诱导独特的肠道病理和粘膜免疫 由宿主因子（IBD），腔内因子（胆汁和微生物组）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患者粪便样品，SARS-COV-2变体， 以及高度可拖动和创新的腔内注射小鼠模型，我们的目的是（1）定义宿主因子 以及与正常和IBD上皮的SARS-COV-2感染有关的细胞机制，（2）确定 肠道SARS-COV-2感染对肠道免疫反应和结肠炎的影响，（3）定义 通过SARS-COV-2影响肠道感染的环境因素。 具有肠生物学，病毒学和粘膜免疫学方面的广泛和协作专业知识（包括 IBD），我们希望解决有关SARS-COV的机械有趣且在临床上重要的问题 2肠感染，免疫反应和肠道病理学。我们期望的知识来自 这项研究将进一步理解与上皮细胞和免疫细胞相互作用 解释有或没有IBD的Covid-19-19 GI症状。我们还期望从该项目中获得的新信息 将扩展我们对急性和慢性胃肠道病理学和covid-19的症状的理解， 提供新颖的策略来减轻Covid-19相关的GI疾病，并创建基础知识 和工具设置，以更深入地研究COVID-19，以及潜在的病原和新兴冠状病毒 未来。