Viral Adaptation to Host Selenium Status

描述(申请人提供)：我们实验室以前的工作已经证明，在缺硒动物中复制的柯萨奇病毒B3人类分离株会产生特定的病毒突变。这些病毒突变导致病毒毒力增加，使通常无毒的病毒变得毒力强。这些相同的特定稳定突变在营养缺乏的条件下反复进化。此外，我们最近还证明，感染柯萨奇病毒A9(另一种人类肠道病毒)的营养不良人群显示出这种病毒快速而显著的序列差异。因此，我们第一次证明了动物和人类的营养状况都可以深刻地影响病毒病原体的基因组，从而导致一种新的病毒株。我们发现宿主营养状态是病毒突变/进化的驱动力，这为我们提出了一个新的研究领域，即宿主营养与病毒进化过程的相互作用。我们认为，宿主的营养状况是病毒出现的一个被低估的因素，我们拥有实验室模型和人类分离株，为阐明营养状况不佳的宿主中病毒群体的行为做出了实质性贡献。这项研究的最终长期目标是在分子水平上确定病毒种群的变化模式，这将有助于识别和预测新的或改变的病原体的出现和传播。我们认为，宿主的营养状况被广泛忽视是病毒进化的驱动力，尽管具有新致病特性的新病毒株和旧病毒株经常出现在普遍营养不良的人群中。因此，我们的研究为理解宿主营养和病毒基因组进化之间的相互作用提供了一个独特的机会。这项拨款是一项跨学科研究，涉及营养学、病毒学、进化生物学和计算生物学等领域。我们的模型系统将从细胞培养研究开始，开发病毒进化的模型，然后通过扩展到动物模型进行测试。最后，我们将使用从导致病毒突变的人类营养压力中获得的病毒分离株来测试我们模型的稳健性。 公共卫生相关性：新出现的传染病是对世界人口的持续威胁。虽然许多因素导致了新病原体的出现，包括旅行、全球变暖、引入新物种等，但寄主的营养状况尚未得到广泛考虑。该项目旨在了解硒营养状况如何影响病毒适应的变化。其目标是开发工具来预测新出现的传染病的爆发。

DESCRIPTION (provided by applicant): Previous work in our laboratory has demonstrated that a human isolate of coxsackievirus B3 replicating in a selenium deficient animal develops specific viral mutations. These viral mutations result in increased virulence of the virus, allowing a normally avirulent virus to become virulent. These same specific stable mutations repeatedly evolve under conditions of nutritional deficiency. In addition, we have recently demonstrated that a nutritionally-deficient human population infected with coxsackievirus A9 (another human enterovirus) exhibited rapid and significant sequence divergence of this virus. Thus, we demonstrated for the first time that the nutritional status of both animals and humans can profoundly influence the genome of a viral pathogen, leading to a new viral strain. Our discovery that host nutritional status is a driving force for viral mutation/evolution, suggested a new area for research, namely the interaction of host nutrition and viral evolutionary processes. We believe that host nutritional status is an underappreciated factor in viral emergence, and that we possess both the laboratory models and the human isolates to make a substantial contribution to elucidating the behavior of virus populations in hosts with suboptimal nutrition. The ultimate, long-term goal of this research is to identify patterns of change in virus populations, on the molecular level, that will facilitate the ability to recognize and predict the emergence and spread of a new or altered pathogen. We propose that host nutritional status has been widely ignored as a driving force for viral evolution, despite the fact that new viral strains, and old viral strains with newly pathogenic properties, often occur in populations with widespread malnutrition. Thus, our studies provide a unique opportunity to understand the interaction between host nutrition and viral genome evolution. This grant is an interdisciplinary study involving the fields of nutrition, virology, evolutionary biology, and computational biology. Our model system will begin as a cell culture study to develop models of virus evolution which will then be tested by expanding into animal models. Finally, we will test the robustness of our models using viral isolates obtained from a human nutritional stress that resulted in viral mutation. PUBLIC HEALTH RELEVANCE: Emerging infectious diseases are a continuing threat to the world's population. Although many factors contribute to the emergence of new pathogens, including travel, global warming, introduction into new species, etc., nutritional status of the host has not been widely considered. This project is designed to understand how selenium nutritional status can impact changes in viral adaptation. The goal is to develop tools to predict outbreaks of emerging infectious diseases.