RAPID: Ecological Dynamics of Human Coronavirus

随着冠状病毒的人畜共患病向人类蔓延以及冠状病毒病（COVID-19）的迅速出现，人类面临着世纪以来的首次全球大流行。目前对传染性病原体SARS-CoV-2的分子、细胞和动物研究使用纯化的病毒储备，而忽略了一种更可能的情况，即自然感染作为活性和缺陷病毒株的混合物传播。该项目正在开发人类冠状病毒的数学模型和湿实验室实验，突出这些菌株与宿主细胞之间的生态相互作用如何严重影响病毒生长，传播和最终导致疾病的能力。所开发的模型解释了缺陷病毒株的存在。该项目结果的更广泛影响将指导临床和一线研究人员直接接触患者，探索更广泛和更深入的感染动力学措施，并应用新的治疗方法。 该项目有可能对制定缓解这一流行病的战略产生重大影响。该项目开发数学模型，并对人类冠状病毒进行湿实验室实验。结果将突出强调菌株与其宿主细胞之间的生态相互作用如何严重影响病毒生长，传播以及最终导致疾病的能力。该项目的目标是：（i）从文献中提取冠状病毒细胞内生长的基本机制和参数，（ii）建立数学模型，解释在不存在和存在缺陷干扰（DI）颗粒的情况下病毒进入、基因表达、基因组复制和颗粒组装的动力学，以及（iii）实施湿实验室实验以证明DI颗粒从冠状病毒培养物中出现，激活免疫细胞因子信号传导，并验证细胞内动力学模型。 该奖项由分子和细胞生物学部门的系统和合成生物学集群颁发，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。

With the zoonotic spillover of coronavirus into humans and the rapid emergence of coronavirus disease (COVID-19), humanity faces its first global pandemic in more than a century. Current molecular, cellular and animal studies of the infectious agent, SARS-CoV-2, use purified virus stocks that ignore a more likely scenario which is that the natural infection spreads as a mixture of active and defective virus strains. This project is developing mathematical models and wet-lab experiments on human coronaviruses that highlight how ecological interactions between such strains and their host cells critically impact the dynamics of virus growth, spread and ultimately their ability to cause disease. The developed models account for the presence of defective virus strains. The broader impact of the results of this project would guide clinical and front-line researchers with direct access to patients, in exploring broader and deeper measures of the infection dynamics and in applying novel therapies. The project has potential to significantly impact the development of strategies that mitigate the pandemic. This project develops mathematical models and performs wet-lab experiments on human coronaviruses. The outcome will highlight how ecological interactions between strains and their host cells could critically impact the dynamics of virus growth, spread and ultimately their ability to cause disease. The project goals are to: (i) extract essential mechanisms and parameters of coronavirus intracellular growth from the literature, (ii) build mathematical models that account for the kinetics of viral entry, gene expression, genome replication and particle assembly in the absence and presence of defective interfering (DI) particles, and (iii) implement wet-lab experiments to demonstrate the emergence of DI particles from coronavirus cultures, activation immune cytokine signaling, and validate the intracellular kinetic models. This RAPID award is made by the Systems and Synthetic Biology Cluster in the Division of Molecular and Cellular Biology, 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.