Influenza A virus replication is dependent on an antioxidant pathway that involves GSH and Bcl-2.
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.
Nencioni
Lucia
L
Department of Experimental Medicine and Biochemical Science, University of Rome La Sapienza, Italy.
Iuvara
Alessandra
A
Aquilano
Katia
K
Ciriolo
Maria R
MR
Cozzolino
Federico
F
Rotilio
Giuseppe
G
Garaci
Enrico
E
Palamara
Anna T
AT
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D009980:Influenza A virus / Q000254:growth & development*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
D000975:Antioxidants; D019253:Proto-Oncogene Proteins c-bcl-2; D014764:Viral Proteins; D005978:Glutathione