Adaptive Immunity and Persistent SARS-CoV-2 Replication

项目概要/摘要 由新型冠状病毒 SARS-CoV-2 (SARS2) 引起的大流行迄今已感染超过 美国有 350 万人死亡，导致超过 138,000 人死亡。尽管有人建议 适应性免疫在改善感染者的临床结果方面发挥着重要作用 SARS2 中，保护性免疫反应尚未明确定义。另外，临床表现也存在差异 SARS2 感染患者的疾病和结果尚未基于定性和结果进行解释 定量抗病毒免疫反应。有趣的是，很大一部分儿童被认为患有 继发于癌症化疗和血液系统疾病的免疫能力缺陷 据观察，病毒可长时间（> 4 周）从上呼吸道排出， 即使临床症状完全缓解后。这一发现提出了一种可能性，即具体 某些个体适应性免疫反应的定性或定量缺陷可能导致 病毒复制的不完全控制和病毒脱落的时间延长。因此，了解 导致控制病毒脱落的免疫反应可能有助于确定保护性的相关性 免疫力，也许更重要的是，确定疫苗限制病毒传播的潜在价值 SARS2 传染给未接种疫苗的人群。我们研究的主要目标是量化适应性免疫 一组具有不同免疫反应水平的儿童对 SARS2 的反应，并将其与 这些对控制上呼吸道病毒脱落的反应，从而允许分层 免疫反应和病毒复制的控制。定义免疫变异之间的关系 能力和病毒脱落可以为适应性水平和性质提供新的见解 免疫力，更具体地说是抗病毒抗体，可以限制或消除 SARS2 中的病毒脱落 感染的患者。我们的研究还将识别在病毒控制不善期间出现的 SARS2 变种 在这些患者中进行复制，因为长期的病毒复制加上无效的免疫力提供了 产生病毒变种的理想机会。从质量和质量方面分析这些变体 SARS2抗体反应的数量将有助于阐明SARS2序列变异的作用和 持续病毒复制作为延长病毒复制的机制。这些研究共同将 检验我们的假设，即免疫反应的变化会导致病毒复制时间延长 和脱落。

Project Summary/Abstract The pandemic caused by the novel coronavirus, SARS-CoV-2 (SARS2) has so far infected greater than 3.5 million individuals and resulted in >138,000 deaths in the US. Although it has been suggested that adaptive immunity plays an important role in improving clinical outcomes of patients infected with SARS2, protective immune responses have not been specifically defined. Also, the variability in clinical disease and outcome in patients with SARS2 infection has not been explained based on qualitative and quantitative antiviral immune responses. Interestingly, a significant proportion of children with presumed deficits in immune competence secondary to cancer chemotherapy and hematologic disorders have been observed to shed virus from the upper respiratory tract for prolonged periods of time (>4 weeks), even after complete resolution of clinical symptoms. This finding raises the possibility that specific qualitative or quantitative deficits in adaptive immune responses in some individuals can result in incomplete control of virus replication and prolonged virus shedding. Therefore, an understanding of the immune responses that lead to control of virus shedding could help define correlates of protective immunity and perhaps more importantly, determine the potential value of vaccines to limit spread of SARS2 to unvaccinated populations. The major goal of our studies is to quantify adaptive immune responses to SARS2 in a cohort of children with varying levels immune responsiveness and to relate these responses to the control of virus shedding in the upper respiratory tract, thus allowing stratification immune reactivity and control of virus replication. Defining relationships between variations in immune competence and virus shedding could provide novel insight into the level and nature of adaptive immunity, more specifically antiviral antibodies, that can restrict or eliminate viral shedding in SARS2 infected patients. Our studies will also identify SARS2 variants that arise during poorly controlled virus replication in these patients as prolonged virus replication coupled with ineffective immunity offers an ideal opportunity for the generation of viral variants. Analysis of these variants in terms of the quality and quantity of SARS2 antibody responses will help elucidate the role of SARS2 sequence variation and persistent virus replication as a mechanism for prolonged virus replication. Together, these studies will test our hypothesis that variations in immune responsiveness contribute to prolonged viral replication and shedding.