Science: The new influenza gene

Brett Jagger and Paul Digard from the University of Edinburgh discovered a new flu gene that hides the 12 genes we know of in the past. This new gene, called PA-X, affects how the viral host reacts to the virus. Curiously, it seems to reduce the severity of the infection.

Science: The new influenza gene

I can write down the entire genome of the flu virus that exists in about one hundred birds, which is only 14,000 bases compared to the human gene, which contains more than 3 billion bases. However, this tiny genetic material is enough to kill thousands of people. Although sequencing is done again and again, we still have a lot of unknowns about it.

A study published in Science magazine is an excellent illustration of the depth of our ignorance. Brett Jagger and Paul Digard from the University of Edinburgh discovered a new flu gene that hides the 12 genes we know of in the past.

This new gene, called PA-X, affects how the viral host reacts to the virus. Curiously, it seems to reduce the severity of the infection. Virologist Ron Fouchier said: "This is indeed an exciting discovery in the flu field." Dendard's old colleague, flu researcher Wendy Barclay from Imperial College London, said: "How can we miss it? It highlights these genomes. How dense is it."


Most influenza viruses belong to influenza A, which can cause a pandemic. Seasonal strains sweep the world every year, and the recently mutated influenza A strain has caused an uproar. Each influenza A virus encapsulates eight RNA strands in a capsid. Some of these chains encode multiple genes, each of which produces a different protein. Until recently, we also thought that the eight chains contained 12 different genes, and the new study increased the number to 13. The results of the study indicate that the flu genome is absolutely full of overlapping instructions.

The following is the mechanism by which it operates. An RNA consisting of a member called a nucleotide is represented by bases A, C, G, and U. One set of three bases corresponds to one amino acid, and the amino acids are connected in series to form a protein. For example, GCA is equal to alanine and AGU is equal to serine. Using this code, you can construct a protein from an RNA sequence by translating the RNA base into an amino acid chain. Of course, it all depends on where you start.

Consider such a short sequence: AGUCCAAGGUAUG. If translation is started from the first base A, serine-valine-lysine-tyrosine can be obtained, leaving a base. However, if translation starts from the second base (G), a completely different chain is obtained: alanine-glutamine-glycine-methionine. The same sequence can be analyzed in as many as three different ways called "reading frames". This is how the flu virus doubles its genetic material, and the same sequence gets the mechanism of both genes.

The new gene discovered by Jagger is another double-browsing. It was found to exist in a third RNA strand that was thought to contain only the PA gene in the past. PA helps the virus replicate the genome. The first time Jagger discovered the quirks about this gene was when he discovered that it was part of an incredible similarity between different strains of influenza. The flu has evolved at an extremely fast rate, so all the determined islands in the changing seas must mean something. Jagger found that this conserved region contains the second gene, PA-X.

RNA is translated into amino acids by a molecular plant called a ribosome. When ribosomes reach a conserved region of PA, they encounter the base CGU, the rarest of all triplets. It drags the ribosome for a long time so that some of it can only move slightly forward. They read the gene from one base along it, creating a completely different amino acid chain. This is PA-X.

Fouchier pointed out that "PA-X preservation in the influenza virus genome clearly indicates that it is important under normal conditions." Its sister gene PA allows the virus to replicate itself, while PA-X has a different role.

It shreds RNA fragments from viral hosts and prevents them from activating their own genes. This process is called host-cell shut-off and is a win-win strategy for viruses. It prevents the host from initiating effective defense against the virus, which means that the host is more likely to use the genetic instructions of the virus to make the protein.

To understand the mechanism by which it helps the virus. Jagger used the 1918 influenza pandemic strain to mutate it so that the PA-X gene no longer functions properly. Without the ability to shut down host reactions, you can expect these mutant viruses to be more easily cleared. However, doing so would make the mutant virus more lethal than the normal 1918 strain, causing more severe weight loss in infected mice, leading to more mouse deaths.

“At first glance, it’s self-contradictory,” Digard said. There appears to be no PA-X, and infected cells activate the immune gene more strongly earlier in the infection process. It triggers a similar reaction to adjacent uninfected cells, leading to an overly strenuous counterattack, ironically causing a more serious disease. This is an experiment showing that PA-X can be regarded as an ambassador of the virus. It manipulates how host gene regulation responds to the virus.

In addition, the new study left us with many questions. “Does the genetic variation of natural PA-X be the cause of some of the different consequences of the disease?” Barclay said. Can we generate better treatment for the flu by targeting this gene? PA significantly affects how avian influenza viruses can replicate in mammalian cells. Does PA-X help the virus cross species barriers? Why is swine flu having a shorter PA-X version than other animals? After decades of research it fainted our minds, and scientists still opened such a very small genome and found treasures of unresolved problems.

Original summary:

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 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.