Investigation of the role of PKC-alpha for influenza A virus-induced signalling and of the inhibitory effect of Verapamil on virus replication
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Influenza Virus (IV) activates the Raf/MEK/ERK-(MAPK) cascade late in theirreplication cycle. This is essential for efficient nuclear RNP-export and therefore forproduction of infectious IV. To characterize cellular factors involved in MAPKactivationin the context of the viral infection I recently analyzed the role of PKC-alpha. Theresults so far indicate, that activation of the Ca2+ activated PKC-alpha is involved in the IVinduced MAPK-signaling and that specific inhibition of this function using a Ca2+channel blocker (Verapamil) at non toxic concentration, negatively affects IVpropagation (265). In addition, I have now further analyzed the action of Verapamil forpossible additional negative effects on IV replication. Therefore I have investigatedviral protein production in IV infected human lung epithelial cell line A549 and foundthat PB1, NP, and NS1 production is significantly reduced in IV infected andVerapamil treated A549 cells. Cell survival and cellular protein production does notseem to be affected ruling out a general effect of Verapamil on translation. Since PB1 isa functional important subunit of the viral polymerase the activity of the polymerasemight be affected. Therefore I analyzed the polymerase activity in Verapamil treatedcells for the production of viral mRNA using primer extension analysis of a reportertranscript expressed by either a plasmid based replication system or in virus infectedcells. My current results show that viral mRNA production in the plasmid based replicationsystem is not affected, while it seems to be reduced in virus infected cells. Thisindicates that Verapamil might alter viral transcription activity in virus infected cells.Taken together, PKC-alpha plays an important role in transmitting the influenza virusinduced signal to the MAPK-cascade. As this PKC-alpha inhibition can be achieved at nontoxicVerapamil concentration, leading to strong reduction of virus titers, inhibition ofthis cellular activity might be a potential anti-viral therapy.Verknüpfung zu Publikationen oder weiteren Datensätzen
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J. Biol. Chem., Vol. 281, 2006, 24, p. 16707-16715