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: 10222232
• 负责人: Christopher L King
• 金额: $ 136.45万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222232
• 关键词: 2019-nCoV; 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; Cells; Clinical; Clinical Trials; Communicable Diseases; Coronavirus Infections; Development; Diagnosis; Disease; Disease Outbreaks; Evaluation; Event; Exposure to; 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; Saliva; Sampling; Secretory Immunoglobulin A; Serologic tests; Severe Acute Respiratory Syndrome; Severity of illness; Shapes; Site; Swab; 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; immunogenicity; indexing; long term memory; male; multidisciplinary; neutralizing antibody; novel; peripheral blood; prevent; prospective; receptor; response; serological marker; transcriptome sequencing; 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.

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 研究的重点是临床疾病患者的免疫反应，但对抗体知之甚少 对COV2的响应，直接在暴露后和发作之前就最早的免疫事件 疾病或无症状的个体以及这如何影响长期免疫记忆。这个建议 在我们的知识中解决这些差距，通过前瞻性跟随家庭接触 COV2确定与这种早期病毒暴露相关的先天和适应性免疫事件 时期。详细评估这些患者的样品，包括外周血细胞和 口服分泌物的蛋白质组学分析，即初始COV2复制的位点。我们将确定是否可能 交叉反应的T细胞和分泌IgA可能有助于这种早期的保护性免疫反应，如果存在 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 研究还将提供有关对COV2的先天免疫反应的详细知识，以及这如何塑造 自然和持续时间的体液免疫。我们的中心假设是外周血淋巴细胞和 在病毒暴露时和开始之前，从个体收集的口咽分泌物 症状将显示与病毒清除率相关的先天和适应性免疫反应 预测是否发展有效的体液免疫和长期免疫记忆。 该假设将通过探索以下目标来解决。 i）评估早期免疫体液和 在诊断为Covid-19的个体的密切接触中，对COV2的细胞免疫反应； ii）评估 早期的先天免疫反应是在诊断为covid-19的个体的密切接触中，并评估他们的 与体液免疫反应和病毒血症的关系； iii）检查早期的体液免疫驱动力 关于免疫记忆的耐用性和对疫苗的反应。对 早期感染与先天感染与自适应免疫对长期记忆和免疫力的关系将会 为开发高度信息和可扩展的血清学测试提供了严格的基础。我们的方法 因此，通过开发和验证新颖的测定法，对RFA-CA-20-039的反应很高 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记 感染和疾病的严重程度。