The human genetic and immunological determinants of the clinical manifestations of SARS-CoV-2 infection: Towards personalised medicine (UNDINE)

接触SARS-CoV-2病毒的后果从没有感染到致命的新冠肺炎。这种巨大的个体间临床变异性是该领域的关键科学和医学谜团。虽然已知年龄和某些合并症会影响疾病结果，但这些参数并不能解释所有的变异。此外，还有其他具有临床重要性的SARS-CoV-2表型：儿童和成人多系统炎症综合征(MIS-C/A)和长冠状病毒病。揭开新冠肺炎发病机制的一个重要突破来自我们的两篇科学论文，这两篇论文被《自然》杂志评为2020年十大发现之一。我们发现，大约4%的重症新冠肺炎肺炎患者存在先天性免疫缺陷，这种缺陷损害了依赖TLR3和IRF7的I型干扰素免疫，至少10%的患者携带已存在的自身抗体(Auto-Abs)中和I型IFN。这些发现为进一步研究新冠肺炎肺炎和其他SARS-CoV-2感染表型铺平了道路，并构成了本研究提案Undine的基础，Undine遵循“床到床”和“床到床”的方法，目的如下：一)破译SARS-CoV-2各种疾病表现的遗传和免疫学基础，识别患严重新冠肺炎、感染后免疫并发症和疫苗失败的风险增加的个人；三)开发即用的诊断试验，用于大规模检测自身抗体对I型IFN的作用，并提出新的预防和治疗方法，基于SARS-CoV-2感染的发病机制，转化为个性化药物。为了实现这些目标，我们的项目将协调欧洲的多学科和翻译研究工作，依靠强大和协同的资产组合，包括来自11个欧盟国家的独特队列和最先进的人类基因、免疫学和病毒学专业知识和技术。

The consequences of SARS-CoV-2 exposure range from a lack of infection to lethal COVID-19. This immense inter-individual clinical variability is the key scientific and medical enigma in the field. While age and certain co-morbidities are known to influence disease outcome, these parameters do not explain all variation. In addition, there are other SARS-CoV-2 phenotypes of clinical importance: multisystem inflammatory syndrome in children and adults (MIS-C/A), and longCOVID. An important breakthrough to unravel the pathogenesis of COVID-19 came from our two Science papers that were recognized by Nature among the top 10 discoveries of 2020. We found that about 4% of patients with critical COVID-19 pneumonia had inborn errors of immunity (IEI) that impair TLR3- and IRF7- dependent type I interferon (IFN) immunity and at least 10% of the patients carried pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs. These findings pave the way for further studies of COVID-19 pneumonia and other SARS-CoV-2 infection phenotypes and form the basis of the present research proposal, UNDINE, which follows a "bed side to bench" and "bench to bed side" approach, with the following objectivies i) to decipher the genetic and immunological basis of the various SARS-CoV-2 disease manifestations, to identify individuals at increased risk of critical COVID-19, post-infectious immunological complications, and vaccine failure iii) to develop ready-to-use diagnostic tests for large-scale detection of auto-Abs to type I IFNs and propose novel preventive and therapeutic approaches, based on the pathogenesis of SARS-CoV-2 infection for translation into personalised medicine. To achieve these goals, our project will coordinate a European multidisciplinary and translational research effort relying on a strong and synergistic combination of assets, including unique cohorts from 11 EU countries and state-of-the art human genetic, immunological and virological expertises and technologies.