EAGER: Integrating Genotype, Phenotype, and Environment to Identify Biomarkers of Coronavirus Disease Severity and Transmission

EAGER：整合基因型、表型和环境来识别冠状病毒疾病严重程度和传播的生物标志物

• 批准号: 2032166
• 负责人: James Weger
• 金额: $ 29.74万
• 依托单位: Virginia Polytechnic Institute and State 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: 2020-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2032166&HistoricalAwards=false
• 关键词: EAGER; Integrating; Genotype; Phenotype; Environment

Proposed in response to a “Dear colleague letter” to fund research to fight the coronavirus pandemic, this project will study the impact of obesity, diabetes, and gender on disease severity and transmission in a mouse model of coronavirus disease. Mouse models must be used to study this disease since humans cannot be infected due to ethical reasons. Obese and diabetic people, along with males, are at a higher risk for severe coronavirus disease, which is concerning since 42% of Americans are obese, 30% are pre-diabetic, and 9.4% have diabetes, while 49.2% are male. It is currently unknown why these groups of people are at higher risk for severe disease, a question that must be answered to develop effective treatments and public health campaigns. The value of this research to the taxpayers is that the information gained will generate data necessary to create effective vaccines and antivirals and identify ways to control coronavirus transmission. In addition, this model will have broad interest to researchers studying the modeling of transmission dynamics, virus-host interactions, immunology, antivirals, and understanding basic virus biology. If successful, these studies will provide a model with the potential to transform the way research with these SARS-CoV-2 is currently done. The borader impacts of this work include mentoring a graduate student and undergraduate students in infectious disease research to train the next generation of STEM researchers.Currently, no models to study the impacts of co-morbidities or identify biomarkers of disease severity or transmission on COVID-19 exist. The goals of this project are to define the impact of obesity, diabetes, and sex on disease severity and transmission in the context of different viral and host genotypes using a natural model of mouse infection with the murine hepatitis virus (MHV). The two strains of mice display differential susceptibility to severe disease to the two strains of mouse coronavirus—from asymptomatic to 80% mortality. Furthermore, MHV is highly transmissible mouse-to-mouse, which is unlikely to occur with SARS-CoV-2 infection in mice. Accordingly, this is an excellent model system with which to gather immunological, viral, and other data from infected mice to identify potential biomarkers of severe disease or transmission. Levels of MHV in the blood and oral passages, gene expression, cytokine levels, blood parameters, clinical disease, tissue pathology, and mortality will be the phenotypes used to compare to disease severity and transmission to identify associations. The hypothesis is that pro-inflammatory cytokines (notably interleukin-6, tumor necrosis factor-alpha, and CXCL10) and concentration of virus in the blood or oral passages can be used to predict disease severity and transmission, respectively. These studies will increase understanding of the underlying biology of coronaviruses, virus and host interactions, the genotype, phenotype, and environmental factors influencing coronavirus disease and transmission, and may identify biomarkers to predict disease severity and transmission in people with COVID-19. This RAPID award is made by the Physiological and Structural Systems Cluster in the BIO Division of Integrative Organismal Systems, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.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.

这个项目是为了回应一封为抗击冠状病毒大流行的研究提供资金的“亲爱的同事信”而提出的，该项目将在冠状病毒疾病的小鼠模型中研究肥胖、糖尿病和性别对疾病严重程度和传播的影响。必须使用小鼠模型来研究这种疾病，因为出于伦理原因，人类不会被感染。肥胖和糖尿病患者以及男性患严重冠状病毒病的风险更高，这一点令人担忧，因为42%的美国人肥胖，30%的人患有糖尿病前期，9.4%的人患有糖尿病，而49.2%的人是男性。目前尚不清楚为什么这些人群患严重疾病的风险更高，这是一个必须回答的问题，以开发有效的治疗方法和公共卫生运动。这项研究对纳税人的价值在于，所获得的信息将产生必要的数据，以创造有效的疫苗和抗病毒药物，并确定控制冠状病毒传播的方法。此外，该模型将对研究传播动力学、病毒-宿主相互作用、免疫学、抗病毒药物和理解基本病毒生物学的建模的研究人员产生广泛的兴趣。如果成功，这些研究将提供一个模型，有可能改变目前对这些SARS-CoV-2进行研究的方式。这项工作的前沿影响包括指导传染病研究的研究生和本科生，以培训下一代STEM研究人员。目前，还没有模型来研究共病的影响，或者在新冠肺炎上识别疾病严重程度或传播的生物标志物。该项目的目标是利用小鼠感染小鼠肝炎病毒(MHV)的自然模型，在不同的病毒和宿主基因型的背景下，确定肥胖、糖尿病和性别对疾病严重性和传播的影响。这两种品系的小鼠对两种品系的小鼠冠状病毒表现出不同的严重疾病敏感性--从无症状到80%的死亡率。此外，MHV是高度可在老鼠之间传播的病毒，这不太可能在小鼠感染SARS-CoV-2时发生。因此，这是一个很好的模型系统，可以用来收集感染小鼠的免疫学、病毒和其他数据，以确定严重疾病或传播的潜在生物标记物。MHV在血液和口腔中的水平、基因表达、细胞因子水平、血液参数、临床疾病、组织病理学和死亡率将被用于比较疾病的严重程度和传播，以确定相关性。假设促炎细胞因子(特别是白介素6、肿瘤坏死因子-α和CXCL10)和血液或口腔中病毒的浓度可以分别用于预测疾病的严重程度和传播。这些研究将增加对冠状病毒的潜在生物学、病毒与宿主的相互作用、影响冠状病毒疾病和传播的基因、表型和环境因素的了解，并可能确定预测新冠肺炎患者疾病严重程度和传播的生物标记物。这一快速奖项是由综合组织系统生物部的生理和结构系统集群利用冠状病毒援助、救济和经济安全(CARE)法案的资金颁发的。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。