Immune Regulation of COVID-19 Infection in Cancer and Autoimmunity

1篇摘要 2 SARS-CoV-2在全球范围内的负面影响在许多不同方面都是天文数字， 社会的三个方面。到目前为止，已经有1300多万人感染，60多万人死亡， 四是占。目前缺乏对病毒调节免疫反应的理解是一个重要的问题。 在缺乏有效的预防、治疗方法的情况下， 6传播与死亡COVID-19疾病在发病率和临床病程方面具有很大的异质性， 7部分种族背景，年龄和预先存在的临床条件。严重的COVID 19和死亡率增加 据报道，癌症患者和非洲裔美国人（AA）中有8例。其中一个共同特点是， 9个人群的炎症基础水平升高，可能与SARS-COV-2驱动的 10炎症导致临床结果不佳。这种促炎环境会加剧淋巴细胞减少 11已经在COVID-19疾病中流行，可能导致T细胞稳态破坏，T细胞帮助差 12和缺乏记忆T和B细胞区室的存活。当前提案的一个核心推论是 具有潜在免疫失调的个体，如癌症患者， 14至COVID-19，介导短期结果不佳和长期免疫记忆受损。到 15直接解决这个问题，我们有机会获得良好的受试者队列，包括AA的高代表性， 16例肺癌和B细胞淋巴瘤。我们的策略将产生B细胞反应的精确定量 17在功能（中和，效应子功能）和细胞水平（B细胞/浆母细胞的深层表型， 18 BCR序列的多样性）。最先进的检测试剂盒，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的 癌症受试者中的炎性环境及其对先天和Tfh功能的影响的分析，以及 21 B细胞和T细胞记忆应答的寿命。将这些B细胞功能的测量（目标1）与 22从OMIC数据（目标2-3）产生的那些将有助于确定 23在癌症背景下增强疾病严重程度的基础。具体而言，我们建议： 1）分析SARS-CoV-2感染后抗原特异性B细胞应答的动力学和持久性 与非癌症患者相比，癌症患者为25例 26 2）确定由普遍存在的炎症环境触发的分子和细胞机制 27例癌症患者在COVID-19期间急性感染损害体液反应 28 3）确定由SARS-CoV-2感染触发的表观遗传和转录机制，和/或 29微生物易位，这将阻碍记忆B和Tfh细胞的寿命。 30这项集体努力旨在阐明COVID-19免疫干预和/或预防的更好途径。 31 32 33叙述 34.这项建议旨在了解癌症患者感染SARS-COV-2的机制基础。 35、导致病情恶化。我们将剖析先天性和适应性免疫反应的特点 36使用无偏见的整体方法来定义癌症宿主环境对定性和定量的影响 保护性记忆T和B细胞反应的37个特征。我们的主要目标是开发新的有效的 38项干预措施，以治疗这一严重受影响的人口。 39 40 41

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