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

SARS-CoV-2 感染临床表现的人类遗传和免疫学决定因素：迈向个性化医疗 (UNDINE)

• 批准号: 10042532
• 金额: $ 22.85万
• 依托单位: IMPERIAL COLLEGE LONDON
• 依托单位国家: 英国
• 项目类别: EU-Funded
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=10042532
• 关键词: human; genetic; immunological; determinants; clinical

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.

接触SARS-CoV-2的后果包括从没有感染到致命的COVID-19。这种巨大的个体间临床差异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covid。我们的两篇科学论文被《自然》评为2020年十大发现之一，这是解开COVID-19发病机制的重要突破。我们发现，约4%的重症COVID-19肺炎患者存在先天性免疫错误（IEI），损害TLR3和IRF7依赖性I型干扰素（IFN）免疫，至少10%的患者携带预先存在的自身抗体（auto-Abs）中和I型IFN。这些发现为进一步研究COVID-19肺炎和其他SARS-CoV-2感染表型铺平了道路，并构成了本研究计划UNDINE的基础，该计划遵循“床侧到工作台”和“工作台到床侧”的方法，其目标如下：(1)破解各种SARS-CoV-2疾病表现的遗传和免疫学基础，识别高危COVID-19、感染后免疫并发症风险增加的个体；iii)根据SARS-CoV-2感染的发病机制，开发用于大规模检测I型干扰素自身抗体的即用型诊断测试，并提出新的预防和治疗方法，以便转化为个性化药物。为了实现这些目标，我们的项目将协调欧洲多学科和转化研究工作，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遗传、免疫学和病毒学专业知识和技术。