tetano
Editor, Senior Moderator
J Virol. 2014 Jan 8. [Epub ahead of print]
Specific residues of PB2 and PA influenza virus polymerase subunits confer the ability for RNA polymerase II degradation and virus pathogenicity in mice.
Llompart CM, Nieto A, Rodriguez-Frandsen A.
Author information
Abstract
Influenza virus transcription requires a functional coupling with cellular transcription for the cap-snatching process. Despite this fact, RNA polymerase II (RNAP II) is degraded during infection in a process triggered by the viral polymerase. Reassortant viruses from A/PR/8/34 (PR8) strain that induce (hvPR8) or not (lvPR8) RNAP II degradation, led to the identification of PA and PB2 subunits as responsible for the degradation process. Three changes in PB2 sequence (I105M, N456D and I504V) and two in PA (Q193H, I550L) differentiate PA and PB2 of lvPR8 from hvPR8. Using recombinant viruses we have observed that changes at positions 504 of PB2 together with 550 of PA confer the ability to lvPR8 for RNAP II degradation and conversely abolish hvPR8 degradation capacity. Since hvPR8 is more pathogenic than lvPR8 in mice, we tested the potential contribution of RNAP II degradation in a distant viral strain such as the 2009 pandemic A/California/04/09 (CAL) virus whose PA and PB2 subunits are of avian origin. As in the hvPR8 virus, mutations at positions 504 of PB2 and 550 of PA in CAL virus abolished its RNAP II degradation capacity. Moreover, in an in vivo model the CAL-infected mice lost more body weight and 75% lethality was observed in this situation compared with 100% survival on mutant CAL- or mock-infected animals. These results confirm the involvement of specific PB2 and PA residues in RNAP II degradation, which correlates with pathogenicity in mice of viruses containing human or avian polymerase PB2 and PA subunits.
PMID:
24403580
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24403580
Specific residues of PB2 and PA influenza virus polymerase subunits confer the ability for RNA polymerase II degradation and virus pathogenicity in mice.
Llompart CM, Nieto A, Rodriguez-Frandsen A.
Author information
Abstract
Influenza virus transcription requires a functional coupling with cellular transcription for the cap-snatching process. Despite this fact, RNA polymerase II (RNAP II) is degraded during infection in a process triggered by the viral polymerase. Reassortant viruses from A/PR/8/34 (PR8) strain that induce (hvPR8) or not (lvPR8) RNAP II degradation, led to the identification of PA and PB2 subunits as responsible for the degradation process. Three changes in PB2 sequence (I105M, N456D and I504V) and two in PA (Q193H, I550L) differentiate PA and PB2 of lvPR8 from hvPR8. Using recombinant viruses we have observed that changes at positions 504 of PB2 together with 550 of PA confer the ability to lvPR8 for RNAP II degradation and conversely abolish hvPR8 degradation capacity. Since hvPR8 is more pathogenic than lvPR8 in mice, we tested the potential contribution of RNAP II degradation in a distant viral strain such as the 2009 pandemic A/California/04/09 (CAL) virus whose PA and PB2 subunits are of avian origin. As in the hvPR8 virus, mutations at positions 504 of PB2 and 550 of PA in CAL virus abolished its RNAP II degradation capacity. Moreover, in an in vivo model the CAL-infected mice lost more body weight and 75% lethality was observed in this situation compared with 100% survival on mutant CAL- or mock-infected animals. These results confirm the involvement of specific PB2 and PA residues in RNAP II degradation, which correlates with pathogenicity in mice of viruses containing human or avian polymerase PB2 and PA subunits.
PMID:
24403580
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24403580