The Influence of Nutrition on Influenza Virus Infection

流感病毒感染每年在世界范围内造成大量发病率和死亡率。流感病毒以改变其基因组而臭名昭著，从而不断地将新的流感病毒株引入人群。由于基因组的变化，感染上一年的流感毒株并不能保证对新毒株有免疫保护。因此，流感研究人员每年都试图预测可能出现的新流感毒株，以便生产疫苗。我们之前对柯萨奇病毒（一种RNA病毒）的研究表明，宿主的营养状况可能影响病毒的基因组。我们能够证明，喂养营养充足的小鼠在感染一种无毒的柯萨奇病毒B3 （CVB3/0）菌株时不会发生心肌炎。然而，当小鼠被喂食缺乏硒（Se）或维生素E的食物时，它们在感染正常良性的CVB3/0后出现心肌炎。这种毒力的变化被发现是由于在缺硒动物体内复制的病毒发生了突变。我们发现从缺硒小鼠分离的病毒中有6个核苷酸发生了变化。在硒充足的小鼠中复制的病毒没有发生变化。这些变化都与病毒的毒力毒株有关。这是第一次证明一种特定的营养缺乏会引起病毒基因组的变化，将一种无毒的病毒变成一种有毒的病毒。本提案旨在将柯萨奇病毒的研究扩展到另一种RNA病毒，即流感病毒。初步结果表明，流感病毒与柯萨奇病毒一样，在缺硒宿主中复制时，会突变为毒性更强的基因型。一旦这些突变发生在缺硒动物身上，即使是正常硒状态的小鼠也容易受到新突变流感病毒毒性增加的影响。本建议旨在确定诱导流感病毒变异的潜在机制。这项工作将有助于进一步了解宿主的营养状况如何不仅影响宿主本身，而且还影响病毒病原体。通过将我们对柯萨奇病毒的观察扩展到一个新的病毒系统，我们可以证明我们的发现不是柯萨奇病毒所独有的，而是可以发生在另一种RNA病毒中。这些发现指出了宿主营养状况在感染期间的重要性，并表明宿主的营养状况也可以通过对病毒基因组的直接影响在新出现的传染病中发挥作用，这是一种以前未知的现象。

Infection with influenza virus causes a great deal of morbidity and mortality worldwide every year. Influenza virus is notorious for changing its genome, thus continually introducing new strains of influenza virus into the population. Because of the genomic changes, infection with an influenza strain from the previous year does not guarantee immune protection from a new strain. Thus, influenza researchers attempt each year to predict the new strain of influenza that may arise in order to produce a vaccine. Our previous work with coxsackievirus, an RNA virus, demonstrated that the nutritional status of the host could influence the genome of the virus. We were able to show that mice fed a nutritionally adequate diet did not develop myocarditis when infected with an avirulent strain of coxsackievirus B3 (CVB3/0). However, when the mice were fed a diet deficient in either selenium (Se) or vitamin E, they now developed myocarditis following infection with the normally benign CVB3/0. This change in virulence was found to be due to mutations that occurred in the virus that repliated in the Se- deficient animals. We found 6 nucleotides had changed in the virus isolated from the Se-deficient mice. No changes occurred in virus which replicated in the Se-adequate mice. These changes were all associated with virulent strains of the virus. This was the first demonstration of a specific nutritional deficiency causing changes in a viral genome, changing an avirulent virus to a virulent one. This proposal is designed to extend our study with coxsackievirus to another RNA virus, namely influenza virus. Preliminary results demonstrate that influenza virus, like coxsackievirus, mutates to a more virulent genotype when replicating in a Se-deficient host. Once these mutations occurred in the Se-deficient animals, even mice with normal Se status are susceptible to the increase virulence of the newly mutated influenza virus. This proposal is designed to determine the underlying mechanism(s) involved in inducing the influenza virus to mutate. This work will lead to a further understanding of how the nutritional status of the host can not only affect the host itself, but also the viral pathogen as well. By extending our observations with coxsackievirus to a new viral system, we can demonstrate that our findings are not unique to coxsackievirus, but rather can occur in another RNA virus. These findings point to the importance of host nutritional status during an infection and demonstrate that the nutritional status of the host can also play a role in emerging infectious diseases by having a direct effect on the genome of a virus, a previously unknown phenomenon.