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

在 COVID-19 的纵向研究中剖析影响严重程度和缓解情况的先天免疫决定因素

• 批准号: MR/V036998/1
• 负责人: Mariola Kurowska-Stolarska
• 金额: $ 60.9万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV036998%2F1
• 关键词: Dissecting; innate; immune; determinants; severity

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).

关于COVID-19的知识差距。髓样细胞在免疫保护中具有重要作用。然而，它们对病原体的强大活性通常受到严格管制。这是因为当这种稳态控制被解除调节时，过度活化的骨髓细胞会损伤组织，例如导致炎性关节疾病。从第一波SARS-CoV-2感染中出现的数据表明，冠状病毒感染后的灾难性组织损伤可归因于骨髓细胞的过度激活，导致呼吸功能不全和严重COVID-19住院治疗。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，我们建议解决关于骨髓细胞在严重COVID-19中的作用的重要和尚未回答的问题。其中包括：（i）我们能否在SARS-CoV-2感染的早期阶段确定可能有助于预测疾病临床进程的骨髓细胞特征？(ii)是什么让骨髓细胞逃脱了通常会减弱病理的稳态调节？(iii)监管机制能否恢复？(iv)骨髓细胞是否保留其异常激活状态（表观遗传学）并导致COVID-19后的长期症状（long-COVID-19）？实验计划。为了解决这一知识缺口，我们将以单细胞分辨率研究COVID-19患者从入院当天到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。我们还将探索（ii）SARS-CoV-2感染是否会诱导骨髓细胞异常激活（表观遗传学）的持久记忆，以及这是否会导致长期COVID-19病理。期待我们预计，我们在骨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骨髓细胞有助于COVID-19疾病进展或消退的新机制。根据这些知识，我们将确定骨髓细胞特征（生物标志物），这些特征可以预测发展严重和/或长期COVID-19的风险，以及新药的治疗靶点，以防止SARS-CoV-2感染期间骨髓细胞的过度激活。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，我们聚集了一支由科学家和临床医生组成的国际研究团队，他们拥有多样化和互补的专业知识。其中包括以下方面的专业知识和设施：骨髓细胞病理学（格拉斯哥大学RACE炎症性关节炎中心与关节炎研究）、COVID-19（意大利罗马Gemelli基金会IRCCS COVID-19学术医院）、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）。

项目成果

Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48.

• DOI: 10.1126/sciadv.abl5182
• 发表时间: 2021-12-10
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Clayton SA;Daley KK;MacDonald L;Fernandez-Vizarra E;Bottegoni G;O'Neil JD;Major T;Griffin D;Zhuang Q;Adewoye AB;Woolcock K;Jones SW;Goodyear C;Elmesmari A;Filer A;Tennant DA;Alivernini S;Buckley CD;Pitceathly RDS;Kurowska-Stolarska M;Clark AR
• 通讯作者: Clark AR

COVID-19 and RA share an SPP1 myeloid pathway that drives PD-L1+ neutrophils and CD14+ monocytes.

• DOI: 10.1172/jci.insight.147413
• 发表时间: 2021-06-18
• 期刊: JCI insight
• 影响因子: 8
• 作者: MacDonald L;Alivernini S;Tolusso B;Elmesmari A;Somma D;Perniola S;Paglionico A;Petricca L;Bosello SL;Carfì A;Sali M;Stigliano E;Cingolani A;Murri R;Arena V;Fantoni M;Antonelli M;Landi F;Franceschi F;Sanguinetti M;McInnes IB;McSharry C;Gasbarrini A;Otto TD;Kurowska-Stolarska M;Gremese E
• 通讯作者: Gremese E

COVID-19 and Rheumatoid Arthritis share myeloid pathogenic and resolving pathways

• DOI: 10.1101/2020.07.26.221572
• 发表时间: 2020-07
• 期刊: bioRxiv
• 作者: L. MacDonald;T. Otto;A. Elmesmari;B. Tolusso;D. Somma;C. McSharry;E. Gremese;I. McInnes;S. Alivernini;M. Kurowska-Stolarska

Pro Nerve Growth Factor and Its Receptor p75NTR Activate Inflammatory Responses in Synovial Fibroblasts: A Novel Targetable Mechanism in Arthritis.

• DOI: 10.3389/fimmu.2022.818630
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Farina L;Minnone G;Alivernini S;Caiello I;MacDonald L;Soligo M;Manni L;Tolusso B;Coppola S;Zara E;Conti LA;Aquilani A;Magni-Manzoni S;Kurowska-Stolarska M;Gremese E;De Benedetti F;Bracci-Laudiero L
• 通讯作者: Bracci-Laudiero L

Using explainable artificial intelligence to predict and forestall flare in rheumatoid arthritis.

使用可解释的人工智能来预测和预防类风湿关节炎的发作。

• DOI: 10.1038/s41591-024-02818-w
• 发表时间: 2024
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Alivernini S