PA from an H5N1 highly pathogenic avian influenza virus activates viral transcription and replication and induces apoptosis and interferon expression at an early stage of infection.
BACKGROUND
Although gene exchange is not likely to occur freely, reassortment between the H5N1 highly pathogenic avian influenza virus (HPAIV) and currently circulating human viruses is a serious concern. The PA polymerase subunit of H5N1 HPAIV was recently reported to activate the influenza replicon activity.


METHODS
The replicon activities of PR8 and WSN strains (H1N1) of influenza containing PA from HPAIV A/Cambodia/P0322095/2005 (H5N1) and the activity of the chimeric RNA polymerase were analyzed. A reassortant WSN virus containing the H5N1 Cambodia PA (C-PA) was then reconstituted and its growth in cells and pathogenicity in mice examined. The interferon promoter, TUNEL, and caspase 3, 8, and 9 activities of C-PA-infected cells were compared with those of WSN-infected cells.


RESULTS
The activity of the chimeric RNA polymerase was slightly higher than that of WSN, and C-PA replicated better than WSN in cells. However, the multi-step growth of C-PA and its pathogenicity in mice were lower than those of WSN. The interferon promoter, TUNEL, and caspase 3, 8, and 9 activities were strongly induced in early infection in C-PA-infected cells but not in WSN-infected cells.


CONCLUSIONS
Apoptosis and interferon were strongly induced early in C-PA infection, which protected the uninfected cells from expansion of viral infection. In this case, these classical host-virus interactions contributed to the attenuation of this strongly replicating virus.
Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 411 Hefei Road, 200025, Shanghai, P. R. China.
Qiang
Q
Wang
Shijian
S
Zhang
Hongbing
H
Jiang
Jinlan
J
Wang
Leiyun
L
Weng
Yingying
Y
Mao
Satoshi
S
Sekiguchi
Fumihiko
F
Yasui
Michinori
M
Kohara
Philippe
P
Buchy
Vincent
V
Deubel
Ke
K
Xu
Bing
B
Sun
Tetsuya
T
Toyoda
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000201:enzymology / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology; D053124:Influenza A Virus, H5N1 Subtype / Q000201:enzymology* / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D007372:Interferons / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000473:pathology / Q000821:virology; D012324:RNA-Dependent RNA Polymerase; D016865:Reassortant Viruses / Q000201:enzymology / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology; D016019:Survival Analysis; D014158:Transcription, Genetic; D019562:Viral Load; D014764:Viral Proteins; D014779:Virus Replication
C061290:PA protein, influenza viruses; D014764:Viral Proteins; D007372:Interferons; D012324:RNA-Dependent RNA Polymerase