Influenza A virus replication is dependent on an antioxidant pathway that involves GSH and Bcl‐2

Abstract

Growing evidence indicates that viral replication is regulated by the redox state of the host cell. We demonstrate that cells of different origins display differential permissivity for influenza A virus replication, depending on their intracellular redox power as reflected by Bcl-2 expression and glutathione (GSH) content. Bcl-2 expressing cells were found to have higher intracellular levels of GSH and to produce lower amounts of virus than Bcl-2 negative cells. Two different steps in the virus life-cycle were involved in Bcl-2/GSH mediated viral inhibition: 1) expression of late viral proteins (in particular hemagglutinin and matrix); and 2) nuclear-cytoplasmic translocation of viral ribonucleoproteins (vRNPs). Buthionine-sulfoximine-induced inhibition of GSH synthesis in Bcl-2 expressing cells caused an increase in the expression of late viral proteins but did not restore vRNP export to the cytoplasm. Collectively, our findings show that both Bcl-2 expression and GSH content contribute to the host cell's ability to down-regulate influenza virus replication, although their effects are exerted at different stages of the viral life-cycle. In certain cell populations, this form of down-regulation might conceivably favor the establishment of persistent viral infection.

Glutathione deficiency in type 2 diabetes impairs cytokine responses and control of intracellular bacteria

“…Our results thus argue for the potential use of that intracellular GSH to GSSG ratio as a reliable biomarker to predict the state of health of the immune system of diabetic patients and their ability to control certain types of intracellular bacterial infections. It remains to be seen whether our prediction model can be extended beyond B. pseudomallei and M. tuberculosis to other bacteria or viruses such as influenza (46).…”

Antioxidant Therapy as a Potential Approach to Severe Influenza-Associated Complications

“…Moreover, both the levels of Bcl-2 expression and the content of intracellular reduced glutathione contribute to the ability of host cells for down-regulating influenza virus replication, although their effects are exerted at different stages of the viral life-cycle [55].…”

Bcl-2 Expression and p38MAPK Activity in Cells Infected with Influenza A Virus

“…In the late phase of replication, newly formed RNP S are transferred from the nucleus to the cytoplasm and packaged into progeny virions (1)(2)(3). Such an essential step in the life cycle of the virus is known to be regulated in part by viral and host cell factors (4 -9), including the expression of Bcl-2, which varies widely from one cell type to another (6,10,11). This transmembrane protein is well known for its ability to prevent the apoptotic cell death provoked by a variety of stimuli (12), a property that is markedly diminished when Bcl-2 undergoes phosphorylation by several different cellular kinases (13)(14)(15)(16).…”