Mechanisms underlying and consequences of hepatic and intestinal manifestations of COVID-19 (C10#)

2019年冠状病毒病（COVID-19）是由冠状病毒（SARS-CoV-2）感染引起的严重急性呼吸道综合征引起的。目前，有效的治疗干预措施的发展是有限的，因为对COVID-19发病机制的重要方面仍不完全了解。呼吸道SARS-CoV-2感染的临床症状包括咳嗽和发热。有趣的是，似乎胃肠道也受到SARS-CoV-2的影响。SARS-CoV-2在COVID-19患者的鼻/咽拭子和粪便中均被检测到，一些研究表明，即使SARS-CoV-2已从呼吸道清除，也可在粪便中长时间检测到。此外，COVID-19患者还经常出现胃肠道症状，包括腹泻或恶心，并显示血清肝转氨酶升高。然而，仍不清楚胃肠道或肝脏的哪些细胞感染了SARS-CoV-2，并导致粪便中存在SARS-CoV-2。此外，肝脏和肠道中相关免疫应答的程度和影响尚不清楚。我们的目标是澄清这些重要问题。CRC 841研究肝脏和肠道炎症，CRC内的研究人员在确定感染的免疫控制以及肝脏和胃肠道炎症性疾病的后果方面具有丰富的经验。因此，我们将利用这一专业知识i）研究SARS-CoV-2利用类器官系统感染人类肝脏和肠细胞的能力; ii）确定免疫细胞，特别是NK细胞识别SARS-CoV-2感染的肠上皮细胞、胆管细胞和肝细胞的能力;和iii）以CD 4 + T辅助细胞和NK细胞为重点，解读SARS-CoV-2感染对肠道炎症和肝脏炎症的影响。总体而言，这些研究将确定COVID-19感染和消化道相关炎症的潜在机制。

Coronavirus disease 2019 (COVID-19) is caused by a severe acute respiratory syndrome induced by an infection with coronavirus (SARS-CoV-2). At present the development of effective therapeutic interventions is limited, as important aspects of COVID-19 pathogenesis remain incompletely understood. Clinical symptoms of respiratory tract SARS-CoV-2 infection include cough and fever. Interestingly, it appears that also the gastrointestinal tract is impacted by SARS-CoV-2. SARS-CoV-2 is detected both in nasal/pharynx swaps and stool of COVID-19 patients, and some studies suggest that SARS-CoV-2 is detectable for extended periods of time in stool, even if it has been cleared from the respiratory tract. Furthermore, COVID-19 patients also frequently suffer from gastrointestinal symptoms including diarrhea or nausea and show increased serum liver transaminases. However, it remains unknown which cells of the gastrointestinal tract or the liver are infected with SARS-CoV-2 and contribute to the presence of SARS-CoV-2 in the stool. Furthermore, the extent and impact of the associated immune responses in liver and intestine are unknown. Our aim is to clarify these important questions. The CRC 841 studies liver and intestinal inflammation, and investigators within the CRC have extensive experience in determining the immune control of infections and consequences for inflammatory diseases of the liver and the GI tract. We will thus use this expertise i) to investigate the ability of SARS-CoV-2 to infect human liver and intestinal cell using organoid systems; ii) to determine the ability of immune cells, in particular NK cells, to recognize SARS-CoV-2-infected intestinal epithelial cells, cholangiocytes and hepatocytes; and iii) to decipher the consequences of SARS-CoV-2 infection on intestinal inflammation and liver inflammation with a focus on CD4+ T helper cells and NK cells. Overall these studies will determine the underlying mechanism for COVID-19 infection and associated inflammation in the digestive tract.