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

COVID-19知识缺口。髓细胞在抗感染的免疫保护中起着重要作用。然而，它们对抗病原体的强大活性通常受到严格监管。这是因为当这种体内平衡控制被解除时，过度激活的骨髓细胞会损害组织，例如导致炎症性关节疾病。来自第一波SARS-CoV-2感染的数据表明，冠状病毒感染后的灾难性组织损伤可归因于骨髓细胞过度激活，导致呼吸功能不全和严重COVID-19住院。迫切需要额外的治疗方法来减轻这种严重程度的进展。通过这个项目，我们建议解决髓系细胞在重症COVID-19中的重要作用和尚未解决的问题。这些问题包括：(i)我们能否在SARS-CoV-2感染的早期阶段识别骨髓细胞的特征，这些特征可能有助于预测疾病的临床病程？（ii）是什么使髓细胞逃避通常会减弱病理的稳态调节？能否恢复管制机制？（iv）骨髓细胞是否保持异常激活状态（表观遗传学）并导致covid -19后长期症状（长- covid -19）？实验计划。为了弥补这一知识空白，我们将在单细胞分辨率下研究COVID-19患者从入院之日到COVID-19后阶段的骨髓细胞变化。我们的具体计划包括(i)研究其分子途径的瞬时变化，特别是应该关闭激活的调节机制。我们还将探讨（ii） SARS-CoV-2感染是否会在髓细胞中诱导异常激活的长期记忆（表观遗传学），以及这是否会导致长期的covid -19病理。期望。我们预计，我们在髓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细胞促进COVID-19疾病进展或解决的新机制。根据这些知识，我们将确定可以预测发生严重和/或长期COVID-19风险的髓细胞特征（生物标志物），以及新药的治疗靶点，以防止SARS-CoV-2感染期间髓细胞过度活化。这些发现的治疗潜力将在实验室的SARS-CoV-2感染的人肺2D和3D模型中进行测试。团队。为了应对这些挑战，我们聚集了一个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。这些专业知识和设施包括：骨髓细胞病理学（炎性关节炎中心与关节炎研究，格拉斯哥大学RACE）， COVID-19 （COVID-19学术医院，意大利罗马Gemelli IRCCS基金会），SARS-CoV-2（格拉斯哥大学病毒研究中心）和表观遗传学（格拉斯哥大学癌症科学研究所）。

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).