Mechanisms of Gastrointestinal COVID-19

胃肠道 COVID-19 的机制

基本信息

批准号：
10467855
负责人：
MATTHEW AARON CIORBA
金额：
$ 58.4万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10467855
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 vaccination CTSL gene Cathepsin L Cell Death Cells Chronic Clinical Colitis Coronavirus Crohn&apos s disease Data Diarrhea Disease Enteral Enterocytes Environmental Risk Factor Epithelial Epithelial Cells Etiology Feces Foundations 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 Nausea and Vomiting Observational Study Organ Organoids Outcome Pathogenesis Pathogenicity Pathology Pathway interactions Patients Pharmacology Phenotype Populations at Risk Reporter Respiratory System Role SARS-CoV-2 infection SARS-CoV-2 variant Sampling Severity of illness Signal Transduction Site Small Intestines Specimen Symptoms Systemic disease Testing Therapeutic Therapeutic immunosuppression Transgenic Mice Tropism Variant Viral Load result Viral reservoir Virus Wild Type Mouse acute infection base 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 invention microbiome microbiome therapeutics microbiota mouse model novel novel coronavirus novel strategies respiratory socioeconomics stool sample tool virology virome virus resource

项目摘要

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.

项目概要尽管 2019 年冠状病毒病 (COVID-19) 主要被定义为一种呼吸道疾病，但高达 50% 的患者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（SARS-CoV-2），该病毒导致 COVID-19 感染人类小肠肠上皮细胞 (IEC) 并在其中复制。然而，分子 SARS-CoV-2 驱动胃肠道病理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。在本提案中，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与 IEC、肠道免疫反应和健康或发炎肠道背景下的微生物组（即，炎症性肠病（IBD））。我们的初步数据表明，与正常的 COVID-19 患者相比，感染前 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 诱导独特的肠道病理和粘膜免疫由宿主因素（IBD）、管腔因素（胆汁盐和微生物组）和治疗决定的反应。具体来说，使用健康的和 IBD 衍生的类器官、COVID-19 患者粪便样本、SARS-CoV-2 变体、和一个高度易于处理和创新的腔内注射小鼠模型，我们的目标是（1）定义宿主因素和涉及正常和 IBD 上皮的 SARS-CoV-2 感染的细胞机制，(2) 确定肠道 SARS-CoV-2 感染对肠道免疫反应和结肠炎的影响，以及 (3) 定义影响 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 的机制上有趣且临床上重要的问题 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了解 SARS-CoV-2 与上皮细胞和免疫细胞的相互作用解释有或没有 IBD 的 COVID-19 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急性和慢性胃肠道病理学以及 COVID-19 症状的了解，提供减轻 COVID-19 相关胃肠道疾病的新策略，并创建基础知识和工具集，用于更深入地研究 COVID-19 以及潜在致病性和新出现的冠状病毒未来。