Adaptive Immunity and Persistent SARS-CoV-2 Replication

项目摘要/摘要 由新型冠状病毒SARS-CoV-2(SARS2)引起的大流行迄今感染的人数超过 在美国，350万人死亡，13.8万人死亡。尽管有人建议， 获得性免疫在改善传染性支气管炎患者临床预后中发挥重要作用 SARS2，保护性免疫反应还没有明确的定义。此外，临床上的可变性 SARS2感染患者的疾病和结局尚未基于定性和 定量的抗病毒免疫反应。有趣的是，有相当大比例的儿童被认为患有 继发于癌症化疗和血液系统疾病的免疫功能缺陷 观察到病毒从上呼吸道排出的时间较长(4周)， 即使在临床症状完全消失之后。这一发现提出了一种可能性，即 某些个体的获得性免疫反应的质或量缺陷可能导致 病毒复制控制不到位，病毒脱落时间延长。因此，理解 导致控制病毒脱落的免疫反应可以帮助确定保护性 免疫力，也许更重要的是，确定疫苗的潜在价值，以限制病毒的传播 向未接种疫苗的人群传播SARS2。我们研究的主要目标是量化适应性免疫。 免疫应答水平不同的儿童对SARS2的反应及其关系 这些对控制病毒在上呼吸道脱落的反应，从而允许分层 免疫反应性和病毒复制的控制。定义免疫变异之间的关系 能力和病毒脱落可以为适应的水平和性质提供新的见解 免疫，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 被感染的病人。我们的研究还将确定在病毒控制不佳期间出现的SARS2变体 在这些患者中复制，因为长期的病毒复制加上无效的免疫提供了一种 这是产生病毒变异的理想机会。分析这些变种的质量和 SARS2抗体反应的数量将有助于阐明SARS2序列变异和 作为延长病毒复制时间的机制的持续病毒复制。总而言之，这些研究将 测试我们的假设，即免疫反应的变化有助于延长病毒复制时间 和脱皮。

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.