EAGER: Investigation of host and viral factors that influence the severity of coronaviral disease

EAGER：研究影响冠状病毒疾病严重程度的宿主和病毒因素

• 批准号: 2031806
• 负责人: James Macy
• 金额: $ 30万
• 依托单位: Yale University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2031806&HistoricalAwards=false
• 关键词: EAGER; Investigation; host; viral; factors

Three coronaviruses (SARS-CoV1, MERS-CoV, and SARS-CoV2) have emerged from animals causing severe respiratory disease in humans. Little is known about the virus-host interactions which control disease severity and transmission, leaving society unprepared for the COVID-19 pandemic. An animal model that closely mimics SARS-CoV-2 infection and pathogenesis is needed to better inform and educate about the science of virus transmission and prevention. Mice are infected with their own, mouse-specific coronavirus [mouse hepatitis virus (MHV)] that causes respiratory disease and affects other organs, such as the heart, liver and spleen, like COVID-19. This proposal will utilize a MHV model of COVID-19 to understand disease progression and the factors involved using controlled conditions. The mouse model takes advantage of available mouse genetic tools, immunologic reagents, and detailed pathologic assessments to identify host factors, such as the type of immune cell infiltrates and cytokines produced that are associated with different disease severities. This analysis will provide insight into protective and deleterious host responses, which can identify processes to target for therapeutics. The development of this model system has the potential to be an efficient and cost effective tool to identify and screen treatment and prevention strategies that warrant escalation to more specific COVID-19 models, thereby making the best use of the limited infrastructure resources associated with the ABSL-3 requirements of actual SARS-CoV2 use. This is a Broader Impact because it will benefit society in the quest for COVID-19 therapeutics and vaccines. Models of all levels of SARS-CoV2 disease in genetically diverse populations are urgently needed. It is hypothesized that the host and virus factors controlling the severity of coronavirus respiratory infections can be identified using natural murine coronavirus infections in diverse, yet genetically defined cohorts of mice. MHV are natural pathogens of mice that are well adapted to their host and vary in both their tropisms and their disease phenotype. The range of pathological lesions and host responses caused by MHV-1 and MHV-A59, with different virulence in the respiratory tract, will be characterized. The eight genetically diverse Collaborative Cross founder mouse strains will be used to represent the genetic diversity seen in large human populations. These studies will focus on lung pathology, but the heart, liver, kidney and spleen will also be evaluated. Mice will be inoculated with MHV-1 or MHV-A59. Tissues will be examined for pathologic changes. Fibrosis and immune cell infiltrates will be characterized using histochemical stains and immunohistochemistry. Viral titers, serum chemistry, coagulation, neutralizing antibodies and cytokines will be measured. Correlations between MHV strain, mouse strain, viral load, clinical disease, pathological lesions, and immune reactions will be determined. These studies are the first step to increase knowledge about the biology of SARS-CoV-2 infections. This RAPID award is made by the Symbiosis, Defense, and Self-recognition Program in the BIO Division of Integrative Organismal Systems, and, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act. It was co-reviewed by the BIO Division of Molecular and Cellular Biology Genetic Mechanisms cluster.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

三种冠状病毒（SARS-CoV 1、MERS-CoV和SARS-CoV 2）已经从动物中出现，导致人类严重的呼吸道疾病。人们对控制疾病严重程度和传播的病毒-宿主相互作用知之甚少，使社会对COVID-19大流行毫无准备。我们需要一种能够模拟SARS-CoV-2感染和发病机制的动物模型，以更好地宣传和教育病毒传播和预防的科学。小鼠感染了自己的小鼠特异性冠状病毒[小鼠肝炎病毒（MHV）]，导致呼吸道疾病并影响其他器官，如心脏，肝脏和脾脏，如COVID-19。该提案将利用COVID-19的MHV模型来了解疾病进展以及使用受控条件所涉及的因素。小鼠模型利用可用的小鼠遗传工具、免疫试剂和详细的病理学评估来鉴定宿主因素，例如与不同疾病严重程度相关的免疫细胞浸润和产生的细胞因子的类型。这种分析将提供对保护性和有害宿主反应的深入了解，这可以识别治疗靶向的过程。该模型系统的开发有可能成为一种高效且具有成本效益的工具，用于识别和筛选需要升级到更具体的COVID-19模型的治疗和预防策略，从而充分利用与实际SARS-CoV2使用的ABSL-3要求相关的有限基础设施资源。 这是一个更广泛的影响，因为它将使社会在寻求COVID-19疗法和疫苗方面受益。 目前迫切需要在遗传多样性人群中建立SARS-CoV2疾病各级模型。据推测，控制冠状病毒呼吸道感染严重程度的宿主和病毒因素可以在不同但遗传上确定的小鼠队列中使用天然鼠冠状病毒感染来鉴定。MHV是小鼠的天然病原体，其很好地适应于其宿主，并且在其嗜性和疾病表型方面都不同。将描述在呼吸道中具有不同毒力的MHV-1和MHV-A59引起的病理损伤和宿主反应的范围。八种遗传多样性的协作交叉创始人小鼠品系将用于代表在大型人群中观察到的遗传多样性。这些研究将侧重于肺部病理学，但也将评估心脏、肝脏、肾脏和脾脏。小鼠将接种MHV-1或MHV-A59。将检查组织的病理变化。将使用组织化学染色和免疫组织化学表征纤维化和免疫细胞浸润。将测量病毒滴度、血清化学、凝血、中和抗体和细胞因子。将确定MHV毒株、小鼠毒株、病毒载量、临床疾病、病理病变和免疫反应之间的相关性。这些研究是增加关于SARS-CoV-2感染生物学知识的第一步。 该RAPID奖项由一体化有机系统生物部的共生、防御和自我认可项目颁发，使用《冠状病毒援助、救济和经济安全（CARES）法案》的资金。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。