Abstract
The PA-X protein, arising from ribosomal frameshift during PA translation, was recently discovered in influenza A virus (IAV). The C-terminal domain ‘X’ of PA-X proteins in IAVs can be classified as full-length (61 aa) or truncated (41 aa). In the main, avian influenza viruses express full-length PA-X proteins, whilst 2009 pandemic H1N1 (pH1N1) influenza viruses harbour truncated PA proteins. The truncated form lacks aa 232–252 of the full-length PA-X protein. The significance of PA-X length in virus function remains unclear. To address this issue, we constructed a set of contemporary influenza viruses (pH1N1, avian H5N1 and H9N2) with full and truncated PA-X by reverse genetics to compare their replication and host pathogenicity. All full-length PA-X viruses in human A549 cells conferred 10- to 100-fold increase in viral replication and 5–8 % increase in apoptosis relative to corresponding truncated PA-X viruses. Full-length PA-X viruses were more virulent and caused more severe inflammatory responses in mice. Furthermore, aa 233–252 at the C terminus of PA-X strongly suppressed co-transfected gene expression by ∼50 %, suggesting that these terminal 20 aa could play a role in enhancing viral replication and contribute to virulence.
Highlights
Influenza A virus (IAV) poses a significant threat to public health and causes considerable economic losses to the livestock industry
There was no significant difference in viral output from Madin-Darby canine kidney cells (MDCK) cells between two forms of pandemic H1N1 (pH1N1), H5N1, and H9N2 viruses (Fig. 2A)
The data from A549 cells showed that pH1N1, H5N1, and H9N2 viruses with full length PA-X appeared to replicate more efficiently than corresponding viruses with truncated PA-X
Summary
Influenza A virus (IAV) poses a significant threat to public health and causes considerable economic losses to the livestock industry. The genome of the influenza virus may encode 10 viral proteins in total, PB2, PB1, PA, HA, NP, NA, M1, M2, NS1, and NS2 [1, 2]. Additional novel proteins have been discovered as a second or third polypeptide made from PB1 and PA mRNA. Some of these proteins, such as PB1-F2 and PA-N155, are virulence factors for the influenza virus [3,4,5]. It has been demonstrated that segment 3 of the influenza A virus encodes the PA protein and an additional novel protein, PA-X, translated as a +1 frameshift open reading frame (X-ORF) extension of a growing PA polypeptide [6]. PA-X in the 1918 pandemic H1N1 virus reduces viral pathogenicity in mice [6]
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