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.

摘要 截至2021年4月30日，COVID-19大流行已导致超过1.48亿例病例和310万例 全球死亡。通常情况下，人们在2至6周后从COVID-19中康复;然而，在很大一部分人中， 患者的症状可能会在最初恢复后持续数周或数月。这些“长COVID-19” SARS-CoV-2感染的症状或急性后遗症（PASC）包括疲劳或肌肉无力，睡眠不足， 疾病，味觉或嗅觉丧失，混乱，焦虑和抑郁。虽然临床特征和 急性COVID-19疾病的发病机制正在深入研究，疾病的长期后果 仍然在很大程度上未知。此外，迄今为止发表的PASC研究报告数量有限 患者出院后的随访时间相对较短;缺乏感染前数据;以及 组织采样有限。在这里，利用最近建立的非人灵长类动物（NHP）模型， 针对SARS-CoV-2感染，我们旨在建立生物安全指南，以验证和标准化PASC NHP 在恒河猴中进行的研究-感染后长达18周-在这些研究中， SARS-CoV-2将从ABSL-3转移到ABSL-2+设施（目标1）。这种将动物从 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， 保护人员和NHP殖民地的安全。将动物转移到BSL-2+将使我们能够 表征在人PASC中观察到的神经和行为表现。此外，我们 在SARS-CoV的长期研究中提出了广泛和最先进的免疫学和病毒学分析， 2-感染的恒河猴（RM），以确定PASC的发病机制并确定其潜在机制 (Aim 2）的情况。重要的是，我们的研究将有助于建立SARS-CoV-2感染的NHP模型， 可能证明对于理解SARS-CoV-2发病机制的长期影响至关重要。该模型提供 疾病发现、发病机制、免疫应答和病毒持久性的纵向评估。 此外，在人体中几乎不可能获得的多种组织的收集，例如肠、脑、心脏和组织。 肺，将使我们能够识别肺和肺外的长期和/或永久性损伤。最后， 纵向和尸检时收集的标本将被冷冻保存，这将是连接我们发现的关键 与SARS-CoV-2恢复期人类队列的数据进行比较。这些研究将使我们能够剖析生物 PASC的潜在原因，从而为预防和治疗长期COVID的影响提供关键见解- 19疾病拟议的研究是在父母奖的范围内，很有可能促进 额外的研究经费导致的进展的总体目标的父母奖。不过有 不与已在母奖中资助的工作重叠。