Identifying immune correlates of disease severity and novel immune drivers of pathogenicity to target in patients with COVID-19

识别疾病严重程度的免疫相关性和新的致病性免疫驱动因素，以针对 COVID-19 患者

• 批准号: 10164208
• 负责人: Ramon E Parsons
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164208
• 关键词: 2019-nCoV; Academic Medical Centers; Administrator; Affect; Algorithms; Basic Science; Blood Vessels; COVID-19; Cancer Patient; Catchment Area; Cities; Clinical Research; Clinical Trials; Collaborations; Communities; Critical Illness; Diagnosis; Disease; Disease Progression; Disseminated Intravascular Coagulation; Education and Outreach; Enrollment; Equipment; Family; Functional disorder; Goals; Health system; Human; Immune; Immune Targeting; Immunologic Monitoring; Immunologics; Immunomodulators; Infection; Inflammatory; Inflammatory Response; Information Technology; Infrastructure; Institutes; Leadership; Lesion; Life; Malignant Neoplasms; Mission; Morbidity - disease rate; New York; Pathogenicity; Pathway interactions; Patients; Phenotype; Physicians; Population; Population Research; Prevention; Principal Investigator; Quality of life; Reporting; Research; Resources; Scientist; Severity of illness; Testing; Translating; Translational Research; Vasculitis; Work; anticancer research; cancer care; cancer education; cancer therapy; cell type; clinical care; cytokine release syndrome; ethnic diversity; immunomodulatory strategy; improved; innovation; lung injury; medical schools; mortality; novel; programs; public health relevance; response; therapeutic target

There is a highly heterogeneous response to infection with SARS-CoV-2 with reports to date suggesting the vast majority of patients are minimally symptomatic, while a significant subset developing life-threatening lung injury associated with hyper-inflammatory response. While initial studies suggested that the cytokine storm was the main driver of lung injuries, more recent observation suggest that vascular lesions leading to severe vasculitis and disseminated intravascular coagulation may also significantly contribute to COVID-19 disease pathophysiology. Regardless of whether the hyperinflammation is causative or reactive, given much of the morbidity and mortality is also associated with hyperinflammation, a better understanding of the immunologic underpinnings of differential responsiveness is necessary to better identify therapeutic targets. Dozens of immunomodulatory agents are rapidly going into clinical trials as well as being used routinely, without a thorough understanding for which inflammatory pathways and cell types to best target, which could be detrimental to critically ill patients. Many of these agents are being tested within the Mount Sinai Health System in New York, a city disproportionately affected by COVID-19. We propose to focus the significant resources of our Human Immune Monitoring Center (HIMC) and the Mount Sinai Cancer Immune Monitoring and Analysis Centers (CIMAC), which have well established and validated platforms to characterize to an unprecedented depth the immune phenotype of SARS-CoV-2 patients at diagnosis and during disease progression with the overarching goal to establish an algorithm to predict disease severity and guide immunomodulatory strategies as well as identify novel immune targets of disease.

对SARS-CoV-2感染的反应具有高度异质性，迄今为止的报告表明，绝大多数患者的症状最小，而一个重要的亚组发生与过度炎症反应相关的危及生命的肺损伤。虽然最初的研究表明细胞因子风暴是肺损伤的主要驱动因素，但最近的观察表明，导致严重血管炎和弥散性血管内凝血的血管病变也可能显著促进COVID-19疾病的病理生理学。无论炎症过度是致病性还是反应性的，鉴于许多发病率和死亡率也与炎症过度相关，更好地理解差异反应性的免疫学基础对于更好地识别治疗靶点是必要的。数十种免疫调节剂正在迅速进入临床试验，并被常规使用，但没有彻底了解哪些炎症途径和细胞类型是最佳靶点，这可能对重症患者有害。其中许多制剂正在纽约的西奈山卫生系统内进行测试，这是一个受COVID-19影响不成比例的城市。我们建议集中我们的人类免疫监测中心（HIMC）和西奈山癌症免疫监测和分析中心（CIMAC）的重要资源，这些研究已经建立了完善的和经过验证的平台，以前所未有的深度表征SARS-CoV的免疫表型，2例患者在诊断时和疾病进展期间，总体目标是建立预测疾病严重程度和指导免疫调节的算法策略以及识别疾病的新免疫靶点。