Dissecting innate immune determinants of severity and resolution in a longitudinal study of COVID-19

新冠肺炎上的知识鸿沟。髓系细胞在抵抗感染的免疫保护中起着重要作用。然而，它们对病原体的强大活性通常受到严格的监管。这是因为当这种体内平衡控制被解除调控时，过度激活的髓系细胞可能会损害组织，例如导致炎症性关节疾病。第一波SARS-CoV-2感染的数据显示，冠状病毒感染后的灾难性组织损害可归因于髓系细胞过度激活，导致住院治疗时出现呼吸功能不全和严重的新冠肺炎。迫切需要额外的治疗方法来减缓这种严重程度的进展。通过这个项目，我们建议解决有关髓系细胞在重症新冠肺炎中的作用的重要和尚未回答的问题。这些包括：(I)我们能否在SARS-CoV-2感染的早期阶段识别髓系细胞的特征，这些特征可能有助于预测临床病程？(Ii)是什么让髓系细胞逃脱了通常会减弱病理的动态平衡调节？(Iii)监管机制能否恢复？(Iv)髓系细胞是否保持其异常的激活状态(表观遗传学)并导致长期的新冠肺炎后症状(新冠肺炎长)？实验计划。为了解决这一认识差距，我们将在单细胞分辨率下调查新冠肺炎患者从入院当天到新冠肺炎后的髓系细胞的变化。我们的具体计划包括(I)研究它们分子通路的瞬时变化，特别是应该关闭激活的调节机制。我们还将探索(Ii)SARS-CoV-2感染是否诱导髓系细胞异常激活(表观遗传学)的长期记忆，以及这是否有助于长期新冠肺炎的病理。期待。我们期待我们在髓系细胞生物学方面的专业知识、经验丰富的临床监测和新技术将发现髓系细胞促进新冠肺炎疾病进展或解决的新机制。从这些知识，我们将确定髓系细胞特征(生物标志物)，可以预测发展成严重和/或长新冠肺炎的风险，以及新药的治疗靶点，以防止在SARS-CoV-2感染期间髓系细胞过度激活。这些发现的治疗潜力将在实验室中用感染SARS-CoV-2的人肺2D和3D模型进行测试。团队。为了应对这些挑战，我们召集了一支由具有多样化和互补性专业知识的科学家和临床医生组成的国际研究团队。这些专家和设施包括：髓系细胞病理学(研究炎性关节炎中心与关节炎，格拉斯哥大学种族)、新冠肺炎(新冠肺炎学术医院，意大利罗马Gemellione IRCCS)、SARS-CoV-2(格拉斯哥大学病毒研究中心)和表观遗传学(格拉斯哥大学癌症研究所)。

The knowledge gap in COVID-19. Myeloid cells have a fundamental role in immune protection against infection. However, their powerful activity against pathogens is usually tightly regulated. This is because when this homeostatic control is deregulated, the over-activated myeloid cells can damage tissues, e.g. resulting in inflammatory joint diseases. Data emerging from the first wave of SARS-CoV-2 infection suggest that the catastrophic tissue damage following coronavirus infection can be attributed to over-activation of myeloid cells, resulting in hospitalisation with respiratory insufficiency and severe COVID-19. There is an urgent need for additional therapeutics to attenuate this progression of severity. With this project, we propose to address important and as-yet unanswered questions about the role of myeloid cells in severe COVID-19. These include: (i) Can we identify characteristics of myeloid cells at an early stage of SARS-CoV-2 infection that might help predict the clinical course of disease? (ii) What allows myeloid cells to escape the homeostatic regulation that would normally attenuate pathology? (iii) Can the regulatory mechanisms be reinstated? (iv) Do myeloid cells retain their aberrant activated state (epigenetics) and contribute to long-term post-COVID-19 symptoms (long-COVID-19)? Experimental plan. To address this knowledge gap, we will investigate the changes in myeloid cells in COVID-19 patients from the day of admission to hospital to post-COVID-19 phase at single cell resolution. Our specific plans include (i) investigating transient changes in their molecular pathways, particularly regulatory mechanisms that should switch-off activation. We will also explore (ii) whether SARS-CoV-2 infection induces long-lasting memory of aberrant activation (epigenetics) in myeloid cells and whether this contributes to long-COVID-19 pathologies. Expectation. We anticipate that our expertise in myeloid cell biology, experienced clinical monitoring and new technologies will discover new mechanisms by which myeloid cells contribute to progression or resolution of COVID-19 disease. From that knowledge we will identify myeloid cell characteristics (biomarkers) that can predict risk of developing severe and/or long COVID-19 and therapeutic targets for new drugs to prevent over-activation of myeloid cells during SARS-CoV-2 infection. The therapeutic potential of these discoveries will be tested in SARS-CoV-2 infected human lung 2D and 3D models in the laboratory. Team. To tackle these challenges, we gathered an international research team of scientists and clinicians with diverse and complementary expertise. These include expertise and facilities in: myeloid cell pathologies (Research into Inflammatory Arthritis Centre Versus Arthritis, RACE, University of Glasgow), COVID-19 (COVID-19 Academic Hospital, Fondazione Gemelli IRCCS, Rome, Italy), SARS-CoV-2 (Centre of Virus Research, University of Glasgow) and epigenetics (Institute of Cancer Sciences, University of Glasgow).