Nutrition, Viral Mutation and Host Defense

描述(申请人提供)：新出现的病毒是一个术语，用于描述新出现在人群中的病毒或正在迅速扩大其范围的病毒。重要的是要了解新的病毒病原体或具有改变致病潜力的旧病毒病原体出现的潜在机制。我们已经证明，宿主的营养状况是新病毒变种出现的驱动力。流感病毒感染缺乏硒(Se)的宿主，与感染Se充足的宿主相比，导致肺病理加重。Se是抗氧化酶谷胱甘肽过氧化物酶和硫氧还蛋白还原酶的重要组成部分。从缺乏硒的宿主中分离出的流感病毒在病毒基因组中发生了特定的突变，导致了更具致病性的病毒株。变异的流感病毒株比原始病毒毒力更强；感染硒状态正常的宿主导致病理加重和严重发病率。这项建议的目的是了解宿主营养状态在促进病毒突变中所涉及的机制(S)。由于涉及的机制(S)可能是多因素的，我们设计了我们的项目来检查三种不同的观点：宿主细胞反应、病毒反应和宿主炎症/先天免疫反应。这种方法认识到病毒本身可能受到宿主营养状况的影响，病毒复制所需的细胞机制可能受到宿主营养状况的影响，最后，对病毒的免疫反应也可能受到宿主营养状况的影响。利用小鼠模型和独特的体外分化的原代人类呼吸道上皮细胞系统，我们可以解决以下问题：1)在缺乏硒的宿主中，流感病毒进化的自然过程是如何改变的？2)与野生型病毒相比，宿主对突变的病毒有何反应？3)防止突变所需的宿主硒的最低水平是多少？4)在防止病毒突变方面，过量的维生素E是否可以弥补缺乏硒的情况？5)宿主缺乏其他抗氧化营养物质(例如维生素C)是否会导致病毒突变9)先天性免疫反应和/或宿主细胞的氧化还原状态是否与诱导缺硒宿主中的病毒突变有关？总而言之，这一跨学科项目将提供有关营养在驱动病毒突变方面的作用的新信息，这些突变最终可能被用于预测和/或预防新的病毒爆发。

DESCRIPTION (provided by applicant): Emerging viruses is a term used to describe viruses that have newly appeared in the population or that are rapidly expanding their range. It is important to understand the underlying mechanisms involved in the emergence of new viral pathogens or old viral pathogens with altered pathogenic potential. We have demonstrated that the nutritional status of the host is a driving force for the emergence of new viral variants. Influenza viral infection of a host deficient in selenium (Se), an essential component of the antioxidant enzymes glutathione peroxidases and thioredoxin reductse, leads to increased lung pathology compared to infected Se-adequate hosts. Influenza viruses isolated from Se-deficient hosts developed specific mutations in the viral genome, resulting in a more pathogenic strain of virus. This mutated influenza virus strain was more virulent than the original virus; infection of hosts with normal Se status resulted in enhanced pathology and severe morbidity. The goal of this proposal is to understand the mechanism(s) involved in the role of host nutritional status in promoting viral mutation. Because the mechanism(s) involved are likely to be multi-factorial, we have designed our project to examine 3 different viewpoints: host cellular responses, viral responses, and host inflammatory/innate immune responses. This approach recognizes that the virus itself may be affected by the nutritional status of the host, that the cellular machinery required for viral replication may be affected by the host nutritional status, and finally that the immune response against the virus may also be influenced by host nutritional status. Using murine models as well as a unique in vitro system of differentiated primary human airway epithelial cells, we can address the following questions: 1) How is the natural course of influenza virus evolution altered in the Se-deficient host? 2) How does the host respond to the mutated virus in comparison with the wild type virus? 3) What is the minimum level of host Se required to prevent the mutations from occurring? 4) Does excess vitamin E compensate for a lack of Se in preventing the viral mutations? 5) Does a host deficiency in other antioxidant nutrients (e.g. vitamin C) lead to viral mutations9 6) Can the innate immune response and/or host cellular redox status be correlated with the induction of viral mutations in the Se-deficient host? Taken together, this interdisciplinary project will provide new information on the role of nutrition in driving viral mutations that may ultimately be used in predicting and/or preventing new viral outbreaks.