Nutrition, Viral Mutation and Host Defense

描述（由申请人提供）：新出现的病毒是一个术语，用于描述在种群中新出现或正在迅速扩大其范围的病毒。重要的是要了解潜在的机制涉及出现新的病毒病原体或旧的病毒病原体改变致病潜力。我们已经证明，宿主的营养状况是新病毒变体出现的驱动力。流感病毒感染缺乏硒（硒是抗氧化酶谷胱甘肽过氧化物酶和硫氧还蛋白还原的重要组成部分）的宿主，与感染硒充足的宿主相比，导致肺部病理增加。从缺硒宿主中分离出的流感病毒在病毒基因组中产生了特定的突变，从而产生了致病性更高的病毒株。这种变异的流感病毒株比原来的病毒毒性更强；硒水平正常的宿主感染后，病理加重，发病率严重。本提案的目的是了解宿主营养状况在促进病毒突变中的作用机制。由于涉及的机制可能是多因素的，我们设计了我们的项目来检查3个不同的观点：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。利用小鼠模型和一种独特的体外分化人气道上皮细胞系统，我们可以解决以下问题：1)流感病毒在缺硒宿主体内进化的自然过程是如何改变的？2)与野生型病毒相比，宿主对突变病毒的反应如何？3)防止突变发生所需的最低宿主硒水平是多少？4)过量的维生素E是否可以弥补硒的缺乏，从而防止病毒突变？5)宿主缺乏其他抗氧化营养素（如维生素C）会导致病毒突变吗？ 6)先天免疫反应和/或宿主细胞氧化还原状态是否与缺硒宿主诱导病毒突变相关？总的来说，这个跨学科项目将提供营养在驱动病毒突变中的作用的新信息，最终可能用于预测和/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.