Gene vital to flu severity discovered

By Helen Albert

Researchers have discovered that a protein known as PA-X, produced from a ribosomal frameshift mutation in a gene in the influenza A genome, has a substantial impact on host response to the virus.

Mice infected with a version of the virus with an active copy of PA-X were more likely to recover and had a less severe disease course than those infected with influenza A with no PA-X expression.

"Just finding this gene in the first place is important, but the find is even more significant because of the role it seems to play in the body's response to flu," study author Paul Digard (University of Edinburgh, UK) commented in a press statement.

Co-author Andrew Firth (University of Cambridge, UK) added: "The flu virus has a very, very small genome - just 12 genes. Finding a new gene makes a pretty significant change to our understanding of this virus."

Writing in Science, the team explains that the influenza A genome subunit 3 produces a single, unspliced messenger RNA (mRNA) that encodes part of the viral RNA-dependent RNA polymerase complex known as PA.

In this study, the researchers discovered a previously unrecognized overlapping open reading frame (X-ORF) that allows the production of an alternative protein product, PA-X, via ribosomal frameshifting.

They found that PA-X acts to limit viral pathogenesis in an infected host by minimizing viral activity and the immune reaction of the host organism.

To test the effects of PA-X, Digard, Firth, and colleagues infected mice with PA-X-positive and PA-X-negative strains of influenza A.

The PA-X-negative virus caused a greater level of disease than the PA-X-positive strain, largely due to an accelerated host immune response to the virus.

"These data contribute substantially to our understanding of influenza A virus replication and pathogenesis and further suggest promising lines of inquiry into the anti-influenza A virus immune response," say Digard, Firth, and team.

They add that their findings suggest that "host immunopathology is of central importance in determining the character of disease and could therefore be a fruitful target for new therapeutics aimed at ameliorating severe influenza A virus illness."

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