Bivalent role of the phosphatidylinositol-3-kinase (PI3K) during influenza virus infection and host cell defence

Abstract

SummaryInfections with influenza A viruses result in the activation of a variety of intracellular signalling pathways. Recent findings suggest that in response to doublestranded RNA (dsRNA), which is commonly used as a mimic for accumulating viral RNA, the phosphatidylinositol-3-kinase (PI3K) is activated and mediates activation of the transcription factor interferon regulatory factor 3 (IRF-3). Thus, we investigated the function of PI3K during influenza virus infection. The pathway was activated upon infection and consistent with earlier findings using dsRNA, inhibition of PI3K itself or block of signalling by the PI3K product, the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), results in misphosphorylation and impaired dimerization of IRF-3 as well as reduced IRF-3-dependent promoter activity. This would imply an antiviral function of the kinase in influenza virusinfected cells. However, upon inhibition of PI3K, titers of progeny virus were reduced rather than enhanced. This was coincident with a strong decrease of viral protein accumulation that was not due to a block of protein synthesis or inhibition of the viral polymerase complex. Immunofluorescence studies revealed that PI3K rather appears to regulate a very early step during viral entry. Thus PI3K is a perfect example of a seemingly antiviral signalling component that is misused by the virus to support effective replication.

Mitogenic stimulation accelerates influenza-induced mortality by increasing susceptibility of alveolar type II cells to infection

“…In addition, it is known that the NS1 protein produced by IAV binds to the p85β subunit of PI3K to induce PI3K activity in infected cells (44). Finally, pharmacological intervention with inhibitors of PI3K and rapamycin block IAV replication in vitro, which is consistent with a role for the PI3K/ Akt/mTOR pathway in IAV infection (33,45).…”

A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection

“…The intensity of the bands was quantitated by an image analyser, and the fold increase in GTP-bound/total Ras is shown at the bottom. former two correspond to the periods before and after replication initiation, respectively 7,22 ( Supplementary Fig. S3d).…”

“…We and others have previously shown that PI3K is required for CIE and influenza virus infection 7,22 , and Epsin1 has been found to be required for virus internalization via CME 5 . However, the molecular mechanisms by which influenza viruses exploit CIE and CME for their efficient internalization by host cells have remained unclear.…”

Deep sequencing of the mouse lung transcriptome reveals distinct long non-coding RNAs expression associated with the high virulence of H5N1 avian influenza virus in mice

“…Most importantly, a number of studies have shown that influenza virus can effectively activate the MAPK pathways and the activation of MAPK family members plays an important role in viral replication, proinflammatory and apoptotic response in various cells during influenza virus infection [69–74]. Moreover, the PI3K/Akt/mTOR pathway also activated during influenza virus infection and function as supporting viral effective replication [75–80]. …”