Role of PI3K/AKT Signaling in the Pathogenesis of Influenza

The influenza A virus is the causative agent of seasonal epidemics and periodic worldwide pandemics. The virus belongs to the Orthomyxoviridae family, with a genome made up of 8 segments of negative-sense RNA that encodes 11 proteins. Influenza virus A infections have been found to induce intracellular signaling pathways that are antiviral in function. However, studies show that some of these signaling pathways are subverted by certain viral genes towards virus supportive functions.The PI3K/AKT signaling pathway is activated upon influenza A virus infection and is required for multiple functions that range from antiviral to proviral. Signaling studies show that virus-induced PI3K/AKT signaling leads to phosphorylation, activation and nuclear translocation of IRF-3. NF-κB is another transcription factor that is similarly activated and translocated to the nucleus. KPNA3, which controls the nuclear import of these transcription factors, has been found to bind a number of influenza proteins like NS1, NP, PB1, PB2 and PA. Within the nucleus, IRF-3 and NF-κB are involved in the expression of pro-inflammatory cytokines such as IFNs and RANTES. Interestingly, the chemokine CCL5 (RANTES) has been shown to provide anti-apoptotic signals for macrophage survival during viral infection.The PI3K/AKT signaling pathway is also involved in proviral activity at various levels. While PI3K and PIP3 appear to control a step in the initial virus uptake at the membrane of cells, PI3K/AKT signaling in later stages of infection has also been well documented. The viral protein NS1 binds to the inter-SH2 domain of the PI3K regulatory subunit p85 leading to PI3K activation. NS1-induced PI3K/AKT activation has been shown to control phosphorylation and inhibition of pro-apoptotic factors like caspase-7 and GSK-3β which eventually result in the suppression of premature apoptosis thus facilitating efficient viral replication. Certain proteins such as MLH1 and PLAC8 which bind PI3K and AKT respectively have recently been shown to also bind a number of influenza proteins such as NP, PB1, PB2 and PA, thus opening up the possibility of further regulation of the PI3K/AKT pathway by the Influenza A virus.