Determination of mucosal immune responses to, and infection of the gastrointestinal tract by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)

项目摘要 在大约6个月内，2019年冠状病毒病（COVID-19）大流行，由严重急性 呼吸道综合征冠状病毒2型（SARS-CoV-2）已导致超过600万例病例，并导致超过35万人死亡 全球范围内，仅美国就有超过10万人死亡。虽然导致这些的主要病理学 死亡是心血管和肺部的性质，COVID-19是一种多系统疾病和胃肠道疾病， (GI)症状经常报告。虽然动物研究和体外实验表明， 肠上皮细胞可被SARS-CoV-2感染，但对人类胃肠道的分析仅限于病毒感染。 粪便中的RNA检测或肠道炎症的建议，如通过粪便中RNA水平升高所测量的。 钙卫蛋白在一个病人的子集。作为纽约市COVID-19病例的最前沿，我们 招募了一组>60人。借助由父R 01支持的强大协作基础架构 资助重点是宿主病毒（HIV-1相关）在胃肠道的相互作用，我们准备详细 COVID-19患者的肠道组织分析。具体而言，如提交的申请所示，我们 已经产生了大量的数据，首次证明了人类肠上皮细胞感染， SARS-CoV-2在某些情况下与肠道炎症证据相关，如粪便检测 钙卫蛋白和许多粪便细胞因子。我们正在确定这些炎症性疾病 免疫应答调节SARS-CoV-2特异性免疫应答，如通过粪便伊加测量的。补充 所要求的资金将使我们能够继续分析已经储存的标本， 能够进一步招募活动期和康复期COVID-19患者。与拟议 研究中，我们的目标是a）进一步表征GI组织的感染; B）确定病毒在肠道中的持久性， 恢复期;和c）确定炎性和抗原特异性粘膜炎症的产生和演变， 免疫反应。总之，通过对这一独特群体的进一步发展和分析，我们的目标是 提供了关于胃肠道在COVID-19发病机制和传播中所起作用的重要见解。

PROJECT SUMMARY In approximately 6 months, the Coronavirus Disease 2019 (COVID-19) pandemic, caused by Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has resulted in >6 million cases and led to >350K deaths worldwide, with over 100K of these deaths in the USA alone. Although the major pathologies leading to these deaths are cardiovascular and pulmonary in nature, COVID-19 is a multi-system disease and gastrointestinal (GI) symptoms are frequently reported. While animal studies and in-vitro experiments demonstrate that enterocytes can be infected by SARS-CoV-2, analyses of the GI tract in humans have been limited to viral RNA detection in feces or suggestions of enteric inflammation as measured by elevated levels of fecal calprotectin in a subset of patients. Being at the forefront of COVID-19 cases in New York City, we have recruited a cohort of >60 individuals. With a strong collaborative infra-structure supported by the parent R01 grant focusing on host-viral (HIV-1 associated) interactions in the GI tract, we are well-poised for detailed analyses of intestinal tissues in COVID-19 patients. Specifically, as evidenced in the submitted application, we have already generated a strong body of data, demonstrating for the first time, human enterocyte infection by SARS-CoV-2 that is in some cases associated with evidence of intestinal inflammation as measured by fecal calprotectin and numerous fecal cytokines. We are in the process of determining how these inflammatory responses modulate SARS-CoV-2 specific immune responses as measured by fecal IgA. The supplementary funds as requested will allow us to continue with the analyses of specimens that are already banked and will enable further recruitment of patients with active and convalescent COVID-19 disease. With the proposed studies, we aim to a) further characterize infection of GI tissues; b) determine viral persistence in the gut during convalescence; and c) determine the generation and evolution of inflammatory and antigen-specific mucosal immune responses. Altogether, through further development and analyses of this unique cohort, we aim to provide important insights into the role played by the GI tract in COVID-19 pathogenesis and transmission.