Project 1: Serological Correlates of SARS CoV2 Immunity and Disease

摘要 人畜共患冠状病毒(CoV)是21世纪三大流行病/大流行的罪魁祸首，包括 2003年严重急性呼吸道冠状病毒(SARS-CoV)与中东呼吸冠状病毒 (MERS-CoV)在2012年。2019年12月，武汉出现了第三种新型冠状病毒，命名为SARS-CoV-2，中国和 已在220个国家造成1300多万例病例和57万人死亡。在不断扩大的美国疫情中，SARS- CoV2已导致137,000人死亡，以及更严重的感染，其特征是肺炎、严重 急性呼吸窘迫综合征(ARDS)、凝固性疾病和炎症性疾病。令人难以置信，小心翼翼 对人畜共患蝙蝠冠状病毒的分析表明，存在大量类似SARS的2b群、类似MERS的2c群 值得注意的是，在原代人类呼吸道或肠道肠样培养中有效复制的第1组菌株。至 为未来的冠状病毒灾难做好准备，明确的诊断分析和血清学调查是必不可少的 跟踪当前和未来的疫情，并评估与以下疾病相关的特定类型和广泛的血清免疫 群体免疫力。该U54中心计划的目标是开发新的针对类型和组的血清学 和中和试验(项目1-Baric，项目2-，核心B和C)，旨在表征血清学 并鉴定关键的区域特异性粘膜和全身性中和和非中和抗体 SARS-CoV-2感染后。一个关键的潜在假设是，IgA和IgG谱在不同的地方是不同的 SARS-CoV2的粘膜和系统区段及靶向唯一和重叠的表位结构域S 糖蛋白。另一个潜在的假设是，干预策略可以改变记忆B细胞和 粘膜和血清中的抗体库。最后，该程序开发了新的鼠标模型 旨在机械地解决基本的免疫、先天和适应性相互作用的人类疾病 与保护性免疫有关。该项目使用新技术、基本和应用战略来建立 绘制、跟踪和治疗未来SARS-CoV2和其他类似SARS的2b组冠状病毒的试剂组合。 在目标1中，我们评估了类型特异性中和抗体反应的动力学、大小和持久性 感染。目的2描述粘膜和系统血清学指标的广度。 肉瘤病毒。在目标3中，我们使用以下方法来表征粘膜和血清中的抗体 各种体外和体内平台，旨在揭示与保护性免疫相关的因素。至 为了实现我们的目标，该项目与中心内的其他项目和核心密切相关。

Abstract Zoonotic coronaviruses (CoV) are responsible for three major epidemics/pandemics in the 21st century, including Severe Acute Respiratory Coronavirus (SARS-CoV) in 2003 and the Middle East Respiratory coronavirus (MERS-CoV) in 2012. In Dec 2019, a third novel CoV designated SARS-CoV-2 emerged in Wuhan China and has caused over 13 million cases, >570,000 deaths in >220 countries. In the expanding US epidemic, SARS- CoV2 has caused >137,000 deaths and significantly more severe infections characterized by pneumonia, severe acute respiratory distress syndrome (ARDS), coagulopathies, and inflammatory disorders. Incredibly, careful analyses of zoonotic bat CoV has revealed the presence of numerous group 2b SARS-like, group 2c MERS-like and remarkably, group 1 strains that replicate efficiently in primary human airway or gut enteroid cultures. To prepare for future CoV calamities, defined diagnostic assays and serologic investigations are essential for tracking current and future outbreaks and evaluate type specific and broad serologic immunity associated with population immunity. The goal of this U54 Center Program is to develop novel type- and group-specific serologic and neutralization assays (Project 1-Baric, Project 2-, Core B and C) designed to characterize the serological repertoire and to identify key domain-specific mucosal and systemic neutralizing and non-neutralizing antibodies after SARS-CoV-2 infection. One key underlying hypothesis is that IgA and IgG repertoires are different across mucosal and systemic compartments and target unique and overlapping epitope domains in the SARS-CoV2 S glycoprotein. Another underlying hypothesis is that intervention strategies can altered the memory B cell and antibody repertoires in mucosal and serologic compartments. Finally the program develops novel mouse models of human disease designed to mechanistically address fundamental immune innate and adaptive interactions associated with protective immunity. The Project uses novel technologies, basic and applied strategies to build a portfolio of reagents that map, track and treat SARS-CoV2 and other SARS-like group 2b CoV of the future. In Aim 1, we evaluate the kinetics, magnitude, durability of type specific neutralizing antibody responses after infection. Aim 2 characterizes the breadth of the mucosal and systemic serologic repertoires across Sarbecoviruses. In Aim 3, we characterize the antibodies in the mucosal and serum serologic repertoires using a variety of in vitro and in vivo platforms, designed to reveal correlates associated with protective immunity. To achieve our goals, the project interfaces closely with other projects and cores within the Center.