Early Drivers of Humoral Immunity to SARS-CoV-2 Infections

SARS-CoV-2 感染体液免疫的早期驱动因素

• 批准号: 10680626
• 负责人: Christopher L King
• 金额: $ 67.96万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10680626
• 关键词: 2019-nCoV; ACE2; Address; Affect; Affinity; Age; Animal Model; Antibodies; Antibody Response; B cell repertoire; B-Lymphocytes; Biological Assay; Biology; Blocking Antibodies; Blood; Blood Cells; Blood Circulation; COVID-19; COVID-19 diagnosis; COVID-19 outbreak; Cells; Clinical; Clinical Trials; Communicable Diseases; Coronavirus Infections; Development; Disease; Evaluation; Event; Female; Frequencies; Future; Generations; Hour; Household; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunologic Memory; Immunologics; Immunology; Impairment; In Vitro; Individual; Infection; Inflammatory Response; Innate Immune Response; Knowledge; Learning; Long-Term Effects; Lymphopenia; Measures; Mediating; Memory; Modeling; Molecular; Molecular Biology; Mucosal Immunity; Mucous Membrane; Nature; Onset of illness; Oral; Oral cavity; Oropharyngeal; Patients; Peripheral; Peripheral Blood Lymphocyte; Peripheral Blood Mononuclear Cell; Post-Translational Protein Processing; Production; Proteins; Proteomics; Public Health; RNA; Role; SARS coronavirus; SARS-CoV-2 exposure; SARS-CoV-2 immunity; SARS-CoV-2 infection; SARS-CoV-2 positive; Saliva; Sampling; Secretory Immunoglobulin A; Serology test; Severity of illness; Shapes; Site; Symptoms; T-Lymphocyte; Testing; Time; Vaccines; Validation; Variant; Viral; Viral Load result; Viral Proteins; Viremia; Virus; adaptive immune response; antigen-specific T cells; cell killing; chemokine; comparative; cross reactivity; cytokine; experience; high risk population; indexing; long term memory; male; multidisciplinary; nasopharyngeal swab; neutralizing antibody; novel; peripheral blood; prevent; prospective; receptor; response; serological marker; transcriptome sequencing; vaccine immunogenicity; virology

The duration and nature of humoral immunity to SARS-CoV-2 (CoV2) infection is poorly understood. Most studies have focused on the immune response in patients with clinical illness, but little is known about antibody response to CoV2 regarding the earliest immunological events immediately after exposure and prior to onset of illness or in asymptomatic individuals and how this impacts long-term immunological memory. This proposal addresses these gaps in our knowledge by prospectively following household contacts with clinical cases of CoV2 to determine innate and adaptive immune events associated with this early viral exposure over a 28 day period. Detailed evaluation of samples from these patients including RNAseq of peripheral blood cells and proteomic analysis of oral secretions, the site of initial CoV2 replication. We will determine whether potentially cross-reactive T cells and secretory IgA may contribute to this early protective immune response and if present do they enhance the subsequent humoral immune responses by providing greater T cell help to B cells. These studies will also provide a detailed knowledge of innate immune responses to CoV2 and how this shapes the nature and duration humoral immunity. Our central hypothesis is that peripheral blood lymphocytes and oropharyngeal secretions collected from individuals at the time of viral exposure and prior to onset of symptoms will show innate and adaptive immune responses that correlate with viral clearance and predict whether or not effective humoral immunity and long-term immunological memory develops. This hypothesis will be addressed by exploring the following aims; i) evaluating the early immune humoral and cellular immune responses to CoV2 in close contacts of individuals diagnosed with COVID-19; ii) to assess early innate immune responses in close contacts of individuals diagnosed with COVID-19 and assess their relationship with humoral immune responses and viremia; and iii) to examine early drivers of humoral immunity on the durability of immunological memory and responses to vaccines. This comprehensive evaluation of the relationships between early infection with innate and adaptive immune on long-term memory and immunity will provide a rigorous basis for the development of highly informative and scalable serological tests. Our approach is therefore highly responsive to RFA-CA-20-039, through the development and validation of novel assays that simultaneously measure innate and adaptive immune responses to CoV2 from early infection; this approach will help define immune parameters and serological markers associated with asymptomatic vs. symptomatic infection and disease severity.

人们对 SARS-CoV-2 (CoV2) 感染的体液免疫的持续时间和性质知之甚少。最多 研究重点关注临床疾病患者的免疫反应，但对抗体知之甚少 暴露后和发病前对 CoV2 的最早免疫学事件的反应 疾病或无症状个体以及这如何影响长期免疫记忆。这个提议 通过前瞻性地跟踪与临床病例有联系的家庭来弥补我们知识上的这些空白 CoV2 用于确定与 28 天内早期病毒暴露相关的先天性和适应性免疫事件 时期。对这些患者样本的详细评估，包括外周血细胞的 RNAseq 和 对口腔分泌物（冠状病毒 2 病毒初始复制位点）进行蛋白质组学分析。我们将确定是否有可能 交叉反应性 T 细胞和分泌性 IgA 可能有助于这种早期保护性免疫反应，如果存在的话 它们是否通过为 B 细胞提供更大的 T 细胞帮助来增强随后的体液免疫反应？这些 研究还将提供对 CoV2 的先天免疫反应的详细知识，以及它如何塑造 体液免疫的性质和持续时间。我们的中心假设是外周血淋巴细胞和 在病毒暴露时和发病前从个体收集的口咽分泌物 症状将显示与病毒清除相关的先天性和适应性免疫反应， 预测是否会形成有效的体液免疫和长期免疫记忆。 这一假设将通过探索以下目标来解决； i) 评估早期免疫体液和 与确诊为 COVID-19 的个体的密切接触者对 CoV2 的细胞免疫反应； ii) 评估 被诊断为 COVID-19 的个体的密切接触者的早期先天免疫反应，并评估其 与体液免疫反应和病毒血症的关系； iii) 检查体液免疫的早期驱动因素 免疫记忆的持久性和对疫苗的反应。本次综合评价 先天性免疫和适应性免疫的早期感染与长期记忆和免疫之间的关系 为开发信息丰富且可扩展的血清学测试提供严格的基础。我们的方法 因此，通过开发和验证新的检测方法，对 RFA-CA-20-039 具有高度响应性 同时测量早期感染对 CoV2 的先天和适应性免疫反应；这种方法 将有助于定义与无症状与有症状相关的免疫参数和血清学标志物 感染和疾病严重程度。