Immune Regulation of COVID-19 Infection in Cancer and Autoimmunity

癌症和自身免疫中 COVID-19 感染的免疫调节

基本信息

批准号：
10222321
负责人：
Rafick Pierre Sekaly
金额：
$ 79.55万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222321
关键词：
2019-nCoV ATAC-seq Address Affect African American Age Aggressive course Anti-Inflammatory Agents Antibodies Antibody Diversity Antibody Formation Antigens Apoptosis Autoimmunity B cell differentiation B-Cell Lymphomas B-Lymphocyte Subsets B-Lymphocytes Bioinformatics Biological Assay COVID-19 Cancer Patient Cell Compartmentation Cell physiology Cells Cessation of life Chromatin Clinical Coculture Techniques Data Death Rate Disease Effector Cell Epigenetic Process Flow Cytometry Gene Expression Profiling Genetic Transcription Goals Homeostasis Immune Immune response Immunologic Memory Immunotherapy Impairment Incidence Individual Infection Inflammasome Inflammation Inflammatory Interferons Intervention Lead Longevity Lymphopenia Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Medical Memory Memory B-Lymphocyte Metabolic Methylation Minor Minority Modification Molecular Monitor Myeloablative Chemotherapy Natural Immunity Obesity Outcome Pathway interactions Patients Phenotype Plasmablast Population Prevalence Prevention Process Radiation therapy Regulatory T-Lymphocyte Reporting Serum Severity of illness Societies T memory cell T-Lymphocyte Testing Therapeutic Vaccines Virus Virus Diseases acute infection adaptive immune response cancer cell cancer immunotherapy cancer therapy cancer type cohort comorbidity coronavirus disease cytokine density effective intervention epigenome functional disability high dimensionality holistic approach immunological intervention immunoregulation inflammatory milieu microbial microbiome monocyte mortality novel outcome forecast prophylactic public health intervention recruit response single-cell RNA sequencing transcriptome transmission process tumor

项目摘要

1 Abstract 2 The negative impact of SARS-CoV-2 worldwide has been astronomical in many different ways, impacting on all 3 aspects of society. Up to date more than 13 million infections and over 600,000 deaths have already been 4 accounted for. The current lack of understanding of the modulation of the immune response by the virus is a 5 dominant factor in the absence of effective prophylactic, therapeutic approaches which can ameliorate virus 6 transmission and mortality. COVID-19 disease is greatly heterogeneous in incidence and clinical course, due in 7 part to ethnic background, age and pre-existing clinical conditions. Severe COVID19 and increased death rate 8 has been reported in cancer patients and in African-Americans (AA). One common feature among these 9 populations is the heightened basal level of inflammation that could synergize with the SARS-COV-2 driven 10 inflammation leading to poor clinical outcomes. This pro-inflammatory milieu will exacerbate the lymphopenia 11 already prevalent in COVID-19 disease and which could lead to disrupted T cell homeostasis, poor T cell help 12 and lack of survival of the memory T and B cell compartments. A central corollary of the current proposal is 13 that individuals with underlying immune dysregulation, such as in cancer, will have abnormal responses 14 to COVID-19, mediating poor short-term outcomes and impairment of long term immune memory. To 15 address this directly, we have access to well-powered cohorts of subjects, including high representation of AA, 16 with lung cancer and B cell lymphomas. Our strategy will generate precise quantification of the B cell response 17 at the functional (neutralization, effector function) and cellular level (deep phenotyping of B cell/plasmablasts, 18 diversity of BCR sequences). State-of-the-art assays including single cell RNAseq, CITEseq, ATACseq, high 19 density flow cytometry, cytokine array, circulating metabolites and microbiome will provide high dimensional 20 analysis of the inflammatory milieu in cancer subjects and its impact on innate and Tfh function as well as 21 longevity of B cell and T cell memory responses. Integration of these measures of B cell function (Aim 1) with 22 those generated from the OMICs data (Aim 2-3) will contribute to the identification of the mechanistic 23 underpinnings that enhance disease severity in the context of cancer. Specifically, we propose to: 24 1) Analyze the dynamics and durability of antigen-specific B cell responses after SARS-CoV-2 infection 25 in cancer patients compared to patients without cancer 26 2) identify the molecular and cellular mechanisms triggered by the inflammatory environment prevalent 27 in cancer patients during acute infection which impairs humoral responses during COVID-19 28 3) Identify the epigenetic and transcriptional mechanisms triggered by SARS-CoV-2 infection and/or 29 microbial translocation that will impede on the longevity of memory B and Tfh cells. 30 This collective effort aims to elucidate better paths for immune intervention and/or prevention in COVID-19. 31 32 33 Narrative 34 This proposal aims at understanding the mechanistic underpinnings of SARS-COV-2 infection in cancer patients 35 which lead to their worsened prognosis. We will dissect features of the innate and adaptive immune responses 36 using unbiased holistic approaches to define the impact of the cancer host milieu on qualitative and quantitative 37 features of the protective memory T and B cell response. Our major goal is to develop novel effective 38 interventions to treat this severely affected population. 39 40 41

1摘要 2全球SARS-COV-2的负面影响在许多不同的方式上都是天文学的，影响了所有人社会的三个方面。最新的感染超过1300万，死亡已经超过60万人 4分。目前缺乏对病毒免疫反应调节的理解是一个 5在没有有效预防性的治疗方法的情况下，可以改善病毒 6传输和死亡率。 COVID-19疾病在发病率和临床过程中非常异质，因此 7部分属于种族背景，年龄和预先存在的临床状况。严重的Covid19和死亡率提高癌症患者和非洲裔美国人（AA）已有8个报道。其中之一 9种群是炎症的基础升高，可以与SARS-COV-2驱动协同 10个炎症导致临床结果不佳。这种促炎的环境将加剧淋巴细胞减少症 11在199疾病中已经普遍存在，可能导致T细胞稳态破坏，T细胞不良帮助 12并且缺乏记忆T和B细胞室的存活。当前提案的中心推论是 13，具有潜在免疫失调的个体（例如癌症）将具有异常反应 14至Covid-19，介导了短期结局不良和长期免疫记忆的损害。到 15直接解决这个问题，我们可以访问众多受试者的队列，包括高度代表AA， 16肺癌和B细胞淋巴瘤。我们的策略将产生B细胞响应的精确量化 17在功能（中和，效应子函数）和细胞水平（B细胞/plasmablasts的深度表型）中， 18 BCR序列的多样性）。最先进的测定法，包括单细胞RNASEQ，Citeseq，Atacseq，高 19密度流式细胞术，细胞因子阵列，循环代谢物和微生物组将提供高维度 20分析癌症受试者中炎症环境及其对先天和TFH功能的影响以及 21 B细胞和T细胞存储器响应的寿命。将B细胞功能的这些度量集成（AIM 1）与 22从OMIC数据产生的那些（AIM 2-3）将有助于识别机械 23在癌症背景下增强疾病严重程度的基础。具体来说，我们建议： 24 1）分析SARS-COV-2感染后抗原特异性B细胞反应的动力和耐用性癌症患者与没有癌症的患者相比25 26 2）确定炎症环境触发的分子和细胞机制急性感染期间癌症患者的27 28 3）确定由SARS-COV-2感染和/或触发的表观遗传和转录机制 29微生物易位会阻碍记忆B和TFH细胞的寿命。 30这项集体努力旨在阐明与19 Covid-19的免疫干预和/或预防的更好的途径。 31 32 33叙事 34该提案旨在了解癌症患者SARS-COV-2感染的机械基础 35导致预后恶化。我们将剖析先天和适应性免疫反应的特征 36使用公正的整体方法来定义癌症宿主环境对定性和定量的影响 37个保护性记忆T和B细胞响应的特征。我们的主要目标是发展有效 38次干预措施，以治疗这一受到严重影响的人群。 39 40 41