Understanding the importance of inflammasomes and interleukin-1 to hyper-inflammatory syndromes, including COVID-19

由严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）引起的COVID-19大流行迄今已在全球造成约90万人死亡。COVID-19的主要死因主要是急性呼吸窘迫综合征（ARDS）和细胞因子风暴综合征（一种导致多器官衰竭的过度炎症状态）。在疫情期间，已经启动了多项临床试验，以治疗患者的过度炎症，以提高死亡率，迄今为止取得了可喜的成果，尽管还没有进行完整的随机3期试验。与风湿性疾病相关的细胞因子风暴并发巨噬细胞活化综合征（MAS）与COVID-19患者中观察到的过度炎症有相当大的生化重叠。有趣的是，药物阿那白滞素，一种重组白细胞介素-1（IL-1）受体拮抗剂，经常在MAS的治疗中使用标签外，并取得了一些成功。然而，对MAS、COVID-19和其他综合征中过度炎症的潜在机制仍知之甚少。因此，更好地了解这些机制可以揭示更有效的治疗方法，并确定那些更有可能对特定治疗（例如阿那白滞素或其他免疫调节剂）作出反应的患者。已经描述了具有人类MAS共同特征的MAS小鼠模型，在本项目中，我们的目标是利用该模型来确定在当前COVID-19大流行和其他综合征中观察到的过度炎症的潜在机制。更具体地说，我们将：1）开发一个药物测试平台，其中：a）新的干预措施为MAS提供了新的机制见解（例如炎性体抑制剂、遗传模型），和B）现有的免疫调节疗法，包括IL-1、IFN γ、TNF α和IL-6的抑制剂，将针对COVID-19和MAS中严重程度的现有和新的血清学预测因子进行测试，2）通过比较老年动物和雄性与雌性小鼠的免疫应答，确定年龄和性别对MAS严重程度的影响。3)通过比较对照小鼠、糖尿病小鼠和高血糖小鼠的免疫反应，确定糖尿病（COVID-19的已知风险因素和共病）对MAS严重程度的影响。该项目的总体成果将是提高对MAS中驱动炎症的调节过程的理解，确定新的治疗策略，以及对性别和共病对过度炎症的影响进行生物学评估

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused ~900k deaths to date worldwide. The main cause of death in COVID-19 is principally through acute respiratory distress syndrome (ARDS) and a cytokine storm syndrome - a state of hyper-inflammation that results in multi-organ failure.Over the course of the pandemic there have been multiple clinical trials initiated to treat patients for hyper-inflammation to improve mortality, with promising results to date, though a full randomised Phase 3 trial has yet to be conducted. Cytokine storm comlicating macrophage activation syndrome (MAS) associated with rheumatic disease, shares considerable biochemical overlap with the hyper-inflammation observed in patients with COVID-19. Interestingly the drug anakinra, a recombinant interleukin-1 (IL-1) receptor antagonist, is often used off-label in the treatment of MAS, with some success. However, the mechanisms underlying the hyper-inflammation in MAS, COVID-19 and other syndromes remain poorly understood. Better understanding of these mechanisms could therefore reveal more effective therapies and identify those patients that are more likely to respond to a particular treatment, for example anakinra or other immune-modulatory agents. A mouse model of MAS with characteristics common to human MAS has been described and in this project we aim to utilise this model to determine mechanisms underlying hyper-inflammation as observed in the current COVID-19 pandemic and other syndromes. More specifically we will:1) Develop a drug testing platform where: a) new interventions providing novel mechanistic insights into MAS (e.g. inflammasome inhibitors, genetic models), and b) existing immunomodulatory therapies including inhibitors of IL-1, IFNy, TNFa, and IL-6, will be tested against existing and new serological predictors of severity in COVID-19 and MAS, and on overall immunology by immunophenotyping bloods.2) Determine the effects of age and gender on MAS severity by comparing immune responses in aged animals and male vs female mice. 3) Determine the effects of diabetes, a known risk factor and co-morbidity for COVID-19, on MAS severity by comparing immune responses in control, diabetic and hyperglycaemic mice. Other relevant co-morbidities may also be studied, for example obesity.The overall outcome of this project will be improved understanding of the regulatory processes driving inflammation in MAS, the identification of new therapeutic strategies, and the biological assessment of the effects of gender and co-morbidity on hyper-inflammation