An imbalance of the intracellular redox state, mainly characterized by glutathione (GSH) depletion, occurs during influenza virus infection and is associated with the progression of disease. The intracellular GSH levels are maintained by the enzymatic activity of glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of pentose phosphate pathway (PPP). Several studies reported an increase in the susceptibility to viral infection in G6PD-deficient individuals even if the mechanisms promoting viral replication are not well defined. Our previous data demonstrated that influenza virus determines a reduction on G6PD expression and activity in human epithelial cell line. These cells, silenced for G6PD and infected with influenza virus, showed an increased expression of viral proteins and viral titer compared to control infected cells.
Interestingly appropriate PPP function and GSH levels are essential for autophagy, a pathway normally activated as host cell response, but used by influenza virus to its own advantage.
On the basis of these evidences in the present proposal we wonder to characterize the mechanisms through which the virus modulates G6PD enzyme and the correlation with the redox changes. Furthermore, we will evaluate whether virus-induced G6PD modulation regulates the autophagic processes. In detail, the specific objectives will be the following:
a) To evaluate the role of virus-induced modulation of G6PD in determining pro-oxidant conditions;
b) To analyze a possible correlation between G6PD modulation and autophagy pathway during influenza virus infection;
c) Since innate immune cells such as macrophage represent the first barrier against influenza A virus, it is interesting to evaluate the effect of the infection on G6PD expression by using macrophage cell line.
Our results will provide new knowledge on the potential correlation between G6PD deficiency, redox state alterations and viral replication in host cells.
Although the association between redox state and viral infections is well-known, the different mechanisms through which the virus may provoke prooxidant condition in the host cell are not well elucidated. Our results will provide new knowledge on a potential mechanism mediated by influenza A virus to both evade host response and to generate the microenvironment ideal for its replication. In fact, it will be deepen the role of G6PD deficiency in the susceptibility to influenza A virus infection in both epithelial and innate immune cell lines. The results obtained from the present proposal will provide new insights on the relationship between redox state, viral replication and host response and will contribute to better understand the mechanisms of pathogenesis of influenza virus.