Bivalent role of the phosphatidylinositol-3-kinase (PI3K) during influenza virus infection and host cell defence.
Infections with influenza A viruses result in the activation of a variety of intracellular signalling pathways. Recent findings suggest that in response to double-stranded 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 virus-infected 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.
Ehrhardt
Christina
C
Institute of Molecular Virology (IMV), ZMBE, Westfaelische-Wilhelms-University, Von-Esmarch-Str. 56, D-48149 Muenster, Germany.
Marjuki
Henju
H
Wolff
Thorsten
T
Nürnberg
Bernd
B
Planz
Oliver
O
Pleschka
Stephan
S
Ludwig
Stephan
S
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004279:DNA, Viral / Q000235:genetics; D004285:Dogs; D004742:Enhancer Elements, Genetic; D004789:Enzyme Activation; D006801:Humans; D009980:Influenza A virus / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication
D004279:DNA, Viral; D050838:Interferon Regulatory Factor-3; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D017346:Protein Serine-Threonine Kinases; D014764:Viral Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate