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7/27/2019 PA-X, A Recently Identified Influenza Gene That Influences Virus Pathogenicity
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PA-X, a recently identified influenza gene that influencesvirus 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
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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 itsown 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 signalingpathways. 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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7/27/2019 PA-X, A Recently Identified Influenza Gene That Influences Virus Pathogenicity
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, a recently identified influenza gene that influences virus pathogenicity | Biochemistry, Molecular, Cellular & Developmental Biology
bmcdb.wordpress.com/2012/06/29/pa-x-a-recently-identified-influenza-gene-that-influences-virus-pathogenicity/[7/17/2013 1:32:49 AM]
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