Developing an NHP model for understanding the biological causes of long COVID-19 pathogenesis

开发 NHP 模型以了解 COVID-19 长期发病机制的生物学原因

• 批准号: 10404760
• 负责人: JONATHAN S LEWIN
• 金额: $ 50万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404760
• 关键词: 2019-nCoV; Abdominal Pain; Accelerometer; Ache; Acute; Age; Animal Model; Animals; Anxiety; Autopsy; Award; Behavioral; Biological; Biological Models; Blood; Bone Marrow; Brain; COVID-19; COVID-19 pandemic; COVID-19 pathogenesis; Caring; Cessation of life; Characteristics; Chest Pain; Chronic; Clinical; Collection; Communities; Confusion; Congestive; Coughing; Critical Illness; Data; Development; Diarrhea; Disease; Echocardiography; Electrocardiogram; Evaluation; Exhibits; Fatigue; Female; Fogs; Fostering; Funding; Goals; Guidelines; Headache; Heart; Hospitalization; Hospitals; Human; Human Resources; Hypertension; Immune; Immune response; Immunologics; Immunology; Impairment; Individual; Infection; Inflammation; Intensive Care; Knowledge; Long COVID; Long-Term Effects; Longitudinal Studies; Lower respiratory tract structure; Lung; Macaca; Macaca mulatta; Measurement; Measures; Medical; Memory; Mental Depression; Mental Health; Modeling; Monitor; Mucous Membrane; Muscle Weakness; Nausea; Neurologic; Neurosciences; Obesity; Parents; Pathogenesis; Pathology; Patient Self-Report; Patients; Prevention strategy; Preventive vaccine; Primates; Procedures; Publishing; Questionnaires; Recovery; Regulation; Reproducibility; Research; Risk Factors; SARS coronavirus; SARS-CoV-2 infection; SARS-CoV-2 negative; SARS-CoV-2 pathogenesis; Safety; Sampling; Scientific Advances and Accomplishments; Shortness of Breath; Sleep; Sleep Disorders; Sleep disturbances; Smell Perception; Specimen; Standardization; Survivors; Swab; Symptoms; Taste Perception; Testing; Therapeutic; Therapeutic Intervention; Tissue Sample; Tissues; Translating; Viral; Viral Pathogenesis; Virus; Work; acute infection; base; cognitive skill; cohort; cost; design; exercise capacity; experience; follow-up; genomic RNA; inflammatory marker; insight; interdisciplinary approach; nonhuman primate; persistent symptom; preservation; prevent; preventive intervention; pulmonary function; research study; sex; therapeutic vaccine; therapeutically effective; virology; virtual

Abstract As of April 30, 2021, the COVID-19 pandemic has resulted in more that 148 million cases and with 3.1 million deaths worldwide. Typically, people recover from COVID-19 after 2 to 6 weeks; however, in a significant fraction of patients symptoms may linger or recur for weeks or months following initial recovery. These “long COVID-19” symptoms or Post-Acute Sequelae of SARS-CoV-2 infection (PASC) include fatigue or muscle weakness, sleep disorders, loss of taste or smell, confusion, anxiety, and depression. While the clinical characteristics and pathogenesis of acute COVID-19 disease are being intensively studied, the long-term consequences of disease remain largely unknown. Furthermore, the small number of PASC research studies published to date are limited by a relatively short follow-up after patients are discharged from the hospital; a lack of pre-infection data; and limited sampling of tissues. Here, taking advantage of a recently established nonhuman primate (NHP) model of SARS-CoV-2 infection, we aim to establish biosafety guidelines to validate and standardize PASC NHP studies in rhesus macaques- up to 18 weeks post-infection – in which animals repeatedly testing negative for SARS-CoV-2 will be transferred from ABSL-3 to ABSL-2+ facilities (Aim 1). This ability to transfer animals from ABSL-3 facilities will be critical to allow the study of PASC in NHP with acceptable costs and labor, while preserving the safety of personnel and the NHP colonies. Transfer of animals to BSL-2+ will allow us to characterize neurological and behavioral manifestations observed in human PASC. Additionally, we are proposing extensive and state-of-the-art immunologic and virologic analyses in a long-term study of SARS-CoV- 2-infected rhesus macaques (RMs) to define the pathogenesis and identify mechanisms underlying PASC (Aim 2). Importantly, our study will contribute to the establishment of NHP models of SARS-CoV-2 infection and could prove essential for understanding long-term effects of SARS-CoV-2 pathogenesis. This model provides longitudinal assessment of disease findings, pathogenesis, immune responses, and viral persistence. Furthermore, collection of multiple tissues virtually impossible to obtain in humans, such as gut, brain, heart and lung, will allow us to identify pulmonary and extra-pulmonary long-term and/or permanent damage. Finally, specimens collected longitudinally and at necropsy will be cryo-banked and will be key in bridging our discoveries with data compiled in SARS-CoV-2 recovery human cohorts. These studies will allow us to dissect biological causes underlying PASC, thus providing key insights for preventing and treating the effects of long-term COVID- 19 disease. The proposed studies are within the scope of the parent award and are highly likely to foster additional research funding leading to the progress of the overall goals of the parent award. However, there is no overlap with work already funded in the parent award.

抽象的 截至 2021 年 4 月 30 日，COVID-19 大流行已导致超过 1.48 亿例病例，其中 310 万例 世界范围内的死亡人数通常会在 2 至 6 周后康复；但是，很大一部分人会在 2 至 6 周后康复； 的患者症状可能会在初次康复后数周或数月内持续或复发。这些“长期 COVID-19”。 SARS-CoV-2 感染 (PASC) 的症状或急性后遗症包括疲劳或肌肉无力、睡眠 紊乱、味觉或嗅觉丧失、精神错乱、焦虑和抑郁。 急性 COVID-19 疾病的发病机制正在深入研究，该疾病的长期后果 此外，迄今为止发表的 PASC 研究数量有限。 患者出院后的随访时间相对较短；以及 在这里，利用最近建立的非人类灵长类动物（NHP）模型。 SARS-CoV-2 感染，我们的目标是建立生物安全指南来验证和标准化 PASC NHP 对恒河猴进行的研究——感染后 18 周——其中动物反复检测呈阴性 SARS-CoV-2 将从 ABSL-3 转移到 ABSL-2+ 设施（目标 1）。 ABSL-3 设施对于以可接受的成本和劳动力在 NHP 中进行 PASC 研究至关重要，同时 保护人员和 NHP 群体的安全 将动物转移到 BSL-2+ 将使我们能够 此外，我们还观察到在人类 PASC 中观察到的特征性神经和行为表现。 提议在 SARS-CoV 的长期研究中进行广泛且最先进的免疫学和病毒学分析 2 感染的恒河猴 (RM) 来定义发病机制并确定 PASC 的潜在机制 （目标 2）重要的是，我们的研究将有助于建立 SARS-CoV-2 感染和 NHP 模型。 该模型对于了解 SARS-CoV-2 发病机制的长期影响至关重要。 对疾病发现、发病机制、免疫反应和病毒持续性的纵向评估。 此外，收集人体中几乎不可能获得的多种组织，例如肠道、大脑、心脏和 肺，将使我们能够识别肺部和肺外的长期和/或永久性损伤。 纵向和尸检时收集的标本将被冷冻保存，这将是弥合我们的发现的关键 这些研究将使我们能够剖析生物学。 导致潜在的 PASC，从而为预防和治疗长期 COVID-19 的影响提供重要见解 19 所提议的研究属于家长奖励的范围，并且极有可能促进疾病的发生。 然而，额外的研究经费导致了母奖总体目标的进展。 与家长奖励中已资助的工作没有重叠。