Host nutritional status is a driving force in influenza A pathogenesis.

摘要

Yearly influenza virus epidemics are associated with a great deal of morbidity and mortality worldwide, with the highest incidences in elderly and chronically ill populations. These two populations are also at high risk for nutritional deficiencies. A high rate of mutation occurs in the genes for two external influenza virus proteins, the hemagglutinin (HA) and the neuraminidase (NA). These two proteins provide the major neutralizing antigenic epitopes for the host immune response and therefore changes in these proteins allow the virus to escape immune detection from a previously infected host. What is the driving force for the mutations? The currently accepted hypothesis is that host immune pressure induces selection of new viral variants. However, this work describes another possibility—that of host antioxidant nutritional status. This work demonstrates that influenza virus replicating in a selenium (Se)-deficient host rapidly mutates to a more pathogenic strain of virus. This increase in pathogenesis was found to be due to changes in the M gene, which codes for the internal matrix protein of the virus. No changes in other viral genes, including the HA and NA, were associated with the change in pathogenicity. Once the changes in the M gene occur, even mice with normal Se status are susceptible to the newly pathogenic properties of the virus. Changes in the M protein increased the fitness level of the virus, which was demonstrated by its ability to outcompete the wildtype virus by replicating faster and to a higher titer. Se is an essential component of the antioxidant enzyme, glutathione peroxidase. Therefore, we hypothesize that a deficiency in Se leads to increased oxidative stress in the infected host, thereby providing a change in the host environment that permits the viral mutations to occur. Based on these findings, we propose that the nutritional status of the host should be considered when exploring mechanisms of viral mutations and emerging infectious diseases. Finally, these results demonstrate a unique mechanism by which viruses can mutate and point to the importance of host antioxidant protection against viral disease.