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/大流行病的罪魁祸首，包括 2003年严重急性呼吸道冠状病毒（SARS-CoV）和中东呼吸道冠状病毒 （MERS-CoV）在2012年。2019年12月，第三种新型冠状病毒SARS-CoV-2在中国武汉出现， 在220多个国家造成了超过1300万例病例，超过57万人死亡。在不断扩大的美国疫情中，SARS- CoV 2已导致> 137，000人死亡，并导致以肺炎为特征的严重感染， 急性呼吸窘迫综合征（ARDS）、凝血病和炎性疾病。难以置信的小心 对人畜共患蝙蝠冠状病毒的分析表明，存在许多2b组SARS样、2c组MERS样 值得注意的是，第1组菌株在原代人气道或肠类培养物中有效复制。到 为未来的CoV灾难做准备，定义的诊断检测和血清学调查是至关重要的， 跟踪当前和未来的疫情，并评估与以下疾病相关的类型特异性和广泛的血清学免疫 群体免疫力。该U 54中心项目的目标是开发新型和组特异性血清学检测试剂盒。 和中和试验（项目1-Baric、项目2-、核心B和C），旨在表征血清学特征 库，并鉴定关键结构域特异性粘膜和全身中和和非中和抗体 感染后的症状一个关键的潜在假设是伊加和IgG库在不同的人中是不同的。 粘膜和全身区室，并靶向SARS-CoV 2 S中独特和重叠的表位结构域 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， 粘膜和血清学区室中的抗体库。最后，该计划开发新的小鼠模型 旨在机械地解决基本的免疫先天性和适应性相互作用 与保护性免疫有关。该项目采用新技术、基本和应用策略， 一系列试剂，用于绘制、跟踪和治疗SARS-CoV 2和未来的其他SARS样2b组CoV。 在目标1中，我们评估了在免疫后型特异性中和抗体应答的动力学、幅度、持久性。 感染目的2描述了粘膜和全身血清学谱的宽度， 肉瘤病毒在目标3中，我们使用以下方法描述粘膜和血清血清学库中的抗体特征： 各种体外和体内平台，旨在揭示与保护性免疫相关的相关性。到 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.