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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

修改后的标题：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修订后的摘要： SARS-CoV-2 是引起冠状病毒病 19 (COVID-19) 的病毒，是一种急性呼吸道感染，超过 90% 的感染者可痊愈，但据报道，该病已进入第二阶段，并累及多个器官。无论年龄或感染严重程度如何，近三分之一的康复者都会出现一系列症状，这些症状通常以持续疲劳和脑雾为特征，临床上被称为“COVID-19长途综合症”。作为 SARS-CoV-2 感染的急性后遗症，症状涉及肺、心脏、脉管系统和中枢神经系统，其潜在机制尚不清楚，但免疫激活/失调与 SARS-CoV-2 病毒残留可能发挥了作用。慢性炎症导致其他健康细胞、组织和器官受损该应用的总体目标是确定感染 SARS-CoV-2 的恒河猴是否能够发展出持续的病理生理学，以重现长新冠病毒的情况。拟议研究的基本原理是基于无论急性 SARS-CoV-2 感染严重程度如何，患者都会出现慢性症状的报告，并且对这种长期疾病状态的生物学基础了解有限，因此迫切需要对此进行研究。了解长新冠病毒并开发一种可用于研究这种综合征的治疗策略的传染病动物模型，我们的次要目标是描绘呼吸道和胃肠道中病毒排出的动力学，以促进恒河猴模型的长期研究。外部限制BSL3 设施。修订后的具体目标：迫切需要对 COVID-19 恒河猴模型进行研究来补充临床数据，因为可以通过纵向功能测试和组织分析来严格评估肺、心脏和大脑内的免疫病理学。急性 SARS-CoV-2 感染恢复后与心肺、免疫和神经系统相关的功能缺陷为了检验这一假设，我们将给一组老年雄性恒河猴接种疫苗。在使用敏感检测确认病毒核酸清除后，将逐步监测动物的心血管和肺功能，以描述 SARS-CoV-2 后的病毒学和免疫学反应如何影响心血管参数。健康和肺功能来指导长新冠病毒的临床表现，我们将完成以下具体目标：目标 1：建立上、下呼吸道病毒核酸持久性和免疫激活的时空动力学我们将在 SARS-CoV-2 感染后对鼻腔、远端肺和直肠中的 SARS-CoV-2 进行连续采样，以使用经过验证的 RT-PCR 方法来量化随时间推移的病毒脱落程度。作为一种基于 CRISPR 的新型免疫分析，将在血液和肺灌洗中进行。目标 2：评估 SARS-CoV-2 感染对心血管和肺功能的影响。基线时以及感染 SARS-CoV-2 后 10 周和 24 周的病毒核酸清除后的心血管测量（超声心动图、多普勒）和肺功能（静态肺力学）目标 3：确定 SARS-CoV 后接种疫苗的影响。 -2 感染对免疫、心血管和肺功能的影响病毒核酸清除后，我们将在感染后 10 周接种疫苗并监测免疫激活/失调、心血管和肺功能。与 SARS-CoV-2。