Credit: James Cavallini/Photo Researchers, Inc.

A recent study identifies a new protein produced by the influenza A virus (IAV) that can modulate the host response, thus providing insights into pathogenesis by this virus (Science 337, 199–204).

Segment 3 of the IAV genome encodes a single mRNA that encodes a subunit of the viral RNA–dependent RNA polymerase complex (PA), and Jagger et al. found that this viral segment contains an additional open reading frame (X-ORF) that can yield a different protein, PA-X, through ribosomal frameshifting. They showed that PA-X is composed of the endonuclease domain of PA and a C-terminal domain encoded by X-ORF and functions to repress the expression of cellular genes.

Jagger et al. then compared the pathology in mice caused by a reconstructed 1918 pandemic IAV that expressed PA-X with mutant IAVs that did not express PA-X. They found that the mutated viruses caused more severe disease than the wild-type 1918 pandemic virus, suggesting that PA-X reduces the pathogenicity of IAV. Moreover, infection with the mutated IAVs was associated with changes in host gene expression, including increased expression of genes involved in inflammation, apoptosis and T cell signaling compared with the wild-type IAV, as well as a reduced ability to induce host-cell shutoff.

This study contributes to our understanding of the roles of the virus and the host immune response in IAV pathogenesis, suggesting that immunopathology is a key aspect of IAV-mediated disease.