Adaptive Immunity and Persistent SARS-CoV-2 Replication

项目概要/摘要 由新型冠状病毒SARS-CoV-2（SARS 2）引起的大流行迄今已感染超过100万人。 3.5在美国，这导致了超过138，000人死亡。尽管有人认为， 获得性免疫在改善感染结核分枝杆菌的患者的临床结果中起重要作用。 SARS 2，保护性免疫反应尚未明确定义。此外，临床上的变异性 尚未根据定性和定性结果解释SARS 2感染患者的疾病和结局 定量抗病毒免疫应答。有趣的是，很大一部分儿童被认为 继发于癌症化疗和血液系统疾病的免疫能力缺陷， 观察到病毒从上呼吸道长时间（>4周）流出， 即使在临床症状完全消退之后。这一发现提出了一种可能性， 某些个体中适应性免疫应答的定性或定量缺陷可导致 病毒复制的不完全控制和延长的病毒脱落。因此， 导致控制病毒脱落的免疫反应可以帮助确定保护性免疫反应的相关性。 免疫力，也许更重要的是，决定疫苗的潜在价值，以限制传播， SARS 2对未接种疫苗的人群。我们研究的主要目标是量化适应性免疫 在具有不同免疫应答水平的儿童队列中对SARS 2的应答， 这些反应控制了上呼吸道中的病毒脱落，从而允许分层 免疫反应性和控制病毒复制。定义免疫系统变异之间的关系 能力和病毒脱落可以提供新的见解的水平和性质的适应性 免疫力，更具体地说是抗病毒抗体，可以限制或消除SARS 2中的病毒脱落 感染的病人。我们的研究还将确定SARS 2变异，这些变异是在病毒控制不佳的情况下出现的。 这些患者中的病毒复制，因为延长的病毒复制加上无效的免疫力， 这是产生病毒变体的理想机会。分析这些变体的质量和 SARS 2抗体应答的数量将有助于阐明SARS 2序列变异的作用， 持续的病毒复制作为延长病毒复制的机制。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 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.