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PA-X, a recently identified influenza gene that influences virus pathogenicity

From “New flu gene found hiding in plain sight, and affects severity of infections” in Discover Magazine

Researchers from the University of Edinburgh have discovered a 13th gene hiding in the tiny influenza genome, PA-X: a gene that can modulate the host cell response to and affects the pathogenicity of the virus.

Image by Doug Jordan, CDC

This new gene, known as PA-X, affects how the virus’s host responds to the virus. Oddly, it seems to reduce the severity of infections. “This is indeed an exciting finding in the flu field,” says virologist Ron Fouchier. “How can we have missed it?” asks Wendy Barclay, a flu researcher from Imperial College London who has worked with Digard before. “It just emphasizes how compact these genomes are.”

Most influenza viruses belong to the influenza A group – these are the ones behind all the big pandemics, the seasonal strains that sweep the world every year, and the mutant strains that have caused such a stir recently. Each influenza A virus is a shell containing eight strands of RNA, a genetic molecule related to DNA. But some of these strands encode multiple genes, each of which produces a different protein. Until recently, we thought that the eight strands contain 12 different genes, and the new study raises that number to 13. The influenza genome, it turns out, is absolutely packed with overlapping instructions.

….

Fouchier notes that “the conservation of PA-X in flu virus genomes certainly suggests that [it] is important under normal circumstances.” But while its sister gene PA allows the virus to copy itself, PA-X has a different role.

It cuts up bits of RNA from the virus’s host, stopping it from activating its own genes. This process, known as host-cell shut-off, is a win-win strategy for the virus. It stops the host from mounting an effective defence against the virus, and it means that the host is more likely to manufacture proteins using the virus’s genetic instructions, rather than its own destroyed RNA.

To understand how this helps the virus, Jagger took the strain of flu behind the 1918 pandemic and mutated it so that the PA-X gene no longer worked properly. Without the ability to shut down the host cell’s response, you’d expect that these mutant viruses would be cleared away more easily. But not so – the mutant virus actually proved to be more deadly than the normal 1918 strain, causing greater weight loss in infected mice, and killing more of them.

“At first sight, it is paradoxical,” says Digard. It seems that without PA-X, the infected cells activate immune genes more intensely and much earlier in the course of infection. This triggers a similar response from nearby uninfected cells, leading to an overly vigorous counter-attack and, ironically, more severe illness. These experiments suggest that PA-X is something of a viral ambassador. It manipulates the host’s genes to control how it responds to the virus.

Here’s a link to the original paper by Jaggar, Wise, et al. 

An Overlapping Protein-Coding Region in Influenza A Virus Segment 3 Modulates the Host Response

Influenza A virus (IAV) infection leads to variable and imperfectly understood pathogenicity. We report that segment 3 of the virus contains a second open reading frame (“X-ORF”), accessed via ribosomal frameshifting. The FS product, termed PA-X, comprises the endonuclease domain of the viral PA protein with a C-terminal domain encoded by the X-ORF and functions to repress cellular gene expression. PA-X also modulates IAV virulence in a mouse infection model, acting to decrease pathogenicity. Loss of PA-X expression leads to changes in the kinetics of the global host response, which notably includes increases in inflammatory, apoptotic, and T-lymphocyte signaling pathways. Thus, we have identified a previously unknown IAV protein that modulates the host response to infection, a finding with important implications for understanding IAV pathogenesis.

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