California National Primate Research Center Development of a Nonhuman Primate Model of Long COVID

加州国家灵长类动物研究中心开发长效新冠病毒非人类灵长类动物模型

• 批准号: 10434302
• 负责人: Prasant Mohapatra
• 金额: $ 49.9万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434302
• 关键词: Address; Age; Alzheimer' s Disease; Anatomy; Appointment; Area; Behavior; Biological Assay; Biomedical Research; California; Caring; Clinical Pathology; Collaborations; Communicable Diseases; Communities; Core Facility; Development; Disease; Ensure; Flow Cytometry; Fostering; Funding; Funding Agency; Genetic; Goals; Grant; Growth; Health; Health Services; Human; Information Technology; Infrastructure; Inhalation Exposure; Institution; Investigation; Knowledge; Laboratories; Lead; Longevity; Lung diseases; Medical; Medicine; Mentors; Mission; Modeling; Multimodal Imaging; National Institute on Aging; Neurosciences; Pilot Projects; Prevention; Primates; Quality of life; Regenerative Medicine; Rejuvenation; Reproductive Sciences; Research; Research Design; Research Personnel; Research Priority; Research Support; Research Training; Resources; Role; Schools; Science; Scientist; Services; Site; Training; Translations; United States National Institutes of Health; Universities; Veterinarians; Vision; ZIKA; animal care; animal facility; base; behavioral health; career; college; design; fighting; high standard; human disease; improved; industry partner; next generation; nonhuman primate; operation; outreach; population health; pre-clinical; programs; psychologic; public-private partnership; recruit; responsible research conduct; success; supportive environment; tool; translational impact; translational scientist

Revised Title: California National Primate Research Center Development of a Nonhuman Primate Model of Long COVID Revised Abstract: SARS-CoV-2, the virus that causes coronavirus disease 19 (COVID-19), is an acute respiratory infection which resolves in more than 90% of infected individuals. However, a second protracted phase of disease with multiorgan involvement has been reported. Regardless of age or infection severity, nearly one-third of recovered individuals report a constellation of symptoms often characterized by persistent fatigue and brain fog. Referred to as “Long COVID” or the “COVID-19 long-hauler syndrome” and clinically as Post-Acute Sequelae of SARSCoV-2 infection, symptoms involve the lungs, heart, vasculature, and the central nervous system. The underlying mechanisms are unknown, but immune activation/dysregulation coupled with SARS-CoV-2 viral remnants may play a role in chronic inflammation resulting in injury to otherwise healthy cells, tissues, and organs. The overall goal of this application is to determine if the SARS-CoV-2 infected rhesus macaque can develop persistent pathophysiology that recapitulates Long COVID in humans. The rationale for the proposed study is based upon reports of patients who develop chronic symptoms regardless of acute SARS-CoV-2 infection severity and a limited understanding of the biological basis for this prolonged disease state. There is therefore an urgent need to understand Long COVID and develop an animal model of infectious disease that can be used to investigate therapeutic strategies for this syndrome. Our secondary objective is to delineate the kinetics of virus shedding in the respiratory and gastrointestinal tract to facilitate long-term studies in the rhesus model outside restricted BSL3 facilities. Revised Specific Aims: Studies in the COVID-19 rhesus macaque model are critically needed to complement clinical data since the immunopathology within the lung, heart, and brain can be rigorously assessed by longitudinal functional testing and tissue analysis. We hypothesize that adult rhesus macaques will develop chronic inflammation and functional deficits associated with the cardiopulmonary, immune and nervous systems following recovery from acute SARS-CoV-2 infection. To test this hypothesis, we will inoculate a cohort of aged male rhesus macaques with SARS-CoV-2 and progressively monitor animals for viral shedding. Assessment of cardiovascular and lung function will be conducted following confirmation of viral nucleic acid clearance using highly sensitive assays. To delineate how virological and immunological responses following SARS-CoV-2 impact parameters of cardiovascular fitness and lung function to direct the clinical manifestations of Long COVID, we will complete the following Specific Aims: Aim 1: Establish spatiotemporal kinetics of viral nucleic acid persistence and immune activation in the upper and lower respiratory tract, and gastrointestinal tract following SARS-CoV-2 infection. We will conduct serial sampling for SARS-CoV-2 in nasal passages, distal lung, and rectum to quantify the degree of viral shedding over time using validated RT-PCR methods as well as a novel CRISPR based assay. Immune profiling will be conducted in blood and lung lavage. Aim 2: Assess the impact of SARS-CoV-2 infection on cardiovascular and pulmonary function. We will assess animals for cardiovascular measures (echocardiogram, doppler) and lung function (static lung mechanics) at baseline and following viral nucleic acid clearance at 10- and 24-weeks post-infection with SARSCoV-2. Aim 3: Determine the impact of vaccination following SARS-CoV-2 infection on immune, cardiovascular and pulmonary function. Following viral nucleic acid clearance, we will vaccinate and monitor immune activation/dysregulation, cardiovascular and lung function at 10-weeks post-infection with SARS-CoV-2.

修订标题： 加利福尼亚州国家灵长类动物研究中心的发展，是长期共同的非人类灵长类动物模型 修订摘要： SARS-COV-2是导致冠状病毒19（COVID-19）的病毒，是一种急性呼吸道感染，可在超过90％的感染个体中解决。然而，已经报道了第二次旷日持久的疾病阶段。不管年龄或感染的严重程度如何，几乎三分之一的被恢复的个体报告的症状星座通常以持续的疲劳和脑雾为特征。被称为“长卷”或“ Covid-19-19-long-Hauler综合征”，在临床上被称为SARSCOV-2感染后的急性后遗症，症状涉及肺，心脏，脉管系统和中枢神经系统。潜在机制尚不清楚，但是与SARS-COV-2病毒残留物相结合的免疫激活/失调可能在慢性感染中起作用，从而导致其他健康细胞，组织和器官受伤。该应用的总体目标是确定SARS-COV-2感染的恒河猴是否可以发展出持续的病理生理学，从而概括了人类长期的covid。拟议研究的基本原理是基于关于急性SARS-COV-2感染严重程度的患者的报道，并且对这种长期疾病状态的生物学基础有限理解。因此，迫切需要理解长期的互联物并发展一种传染病的动物模型，该模型可用于研究该综合征的理论策略。我们的次要目标是描述呼吸道和胃肠道的病毒脱落的动力学，以在恒河所模型的长期研究中，在受限的BSL3设施之外进行了长期研究。 修订的具体目的： 在COVID-19中进行的研究需要严格地补充临床数据，因为可以通过纵向功能测试和组织分析对肺，心脏和大脑内的免疫病理进行严格评估。我们假设成年恒河猕猴将在急性SARS-COV-2感染中恢复后，会发展与心肺，免疫和神经系统相关的慢性感染和功能缺陷。为了检验这一假设，我们将用SARS-COV-2接种一组老年男性恒河猕猴，并逐步监测动物的病毒脱落。使用高度敏感的评估确认病毒核酸清除率后，将对心血管和肺功能进行评估。 To delineate how virological and immunological responses following SARS-CoV-2 impact parameters of cardiovascular fitness and lung function to direct the clinical manifestations of Long COVID, we will complete the following Specific Aims: Aim 1: Establish spatial temporal kinetics of viral nuclear acid persistence and immuno activation in the upper and lower respiratory tract, and gastrointestinal tract following SARS-CoV-2 infection.我们将使用经过验证的RT-PCR方法以及一种基于CRISPR的新型测定法对SARS-COV-2进行SARS-COV-2的串行采样，以量化随时间的病毒脱落程度。免疫分析将在血液和肺灌洗中进行。 AIM 2：评估SARS-COV-2感染对心血管和肺功能的影响。我们将评估动物的心血管测量值（超声心动图，多普勒）和基线时的肺功能（静态肺机制），并在与SARSCOV-2感染后10岁和24周在10岁和24周病毒核酸清除率后进行病毒核酸清除率。 AIM 3：确定SARS-COV-2感染后疫苗接种对免疫学，心血管和肺功能的影响。病毒核酸清除率后，我们将接种疫苗并监测免疫学激活/失调，心血管和肺功能在10周感染后与SARS-COV-2。