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International Team Detects Gene Variant Influencing Flu Susceptibility

NEW YORK (GenomeWeb News) – A variant in a gene called IFITM3 appears to mediate at least some variability in human influenza virus susceptibility, according to a study online yesterday in Nature by investigators from the UK, US, and Italy.

Motivated by past genomic screening and cell line experiments showing that the IFITM3 gene product affects the ability of influenza A and some other viruses to enter and replicate in host cells, the researchers did a series of experiments in mouse models before turning their attention to patients at hospitals in England and Scotland who were infected with the 2009 H1N1 pandemic influenza A strain between late 2009 and early 2011.

Just as mice that didn't produce the IFITM3 gene product were more prone to serious flu symptoms, a specific IFITM3 allele appeared much more frequently amongst hospitalized H1N1 patients than it did in the general population, they found.

"We think that variants in IFITM3 may be part of the story of why some individuals don't cope so well with influenza infection," co-corresponding author Paul Kellam, a researcher affiliated with the Wellcome Trust Sanger Institute and University College London, said during a telephone briefing with reporters.

The work stemmed from a broader study on the biological underpinnings of the H1N1 pandemic flu virus that circulated from about 2009 on. Though it produced fairly mild and manageable symptoms in most people, the H1N1 virus led to hospitalization and even death for a subset of those infected with it, Kellam noted, leaving researchers to puzzle over what host features might be behind this difference in disease symptoms and susceptibility.

"People, when they get very sick with the flu tend to assume that they got a very nasty virus," co-author Kenneth Baillie, a researcher with the Roslin Institute and the University of Edinburgh, said during the teleconference. "But in fact, everyone got very similar viruses and some people barely noticed whereas some became desperately ill."

The group started out by doing experiments on a mouse model already developed in co-author David Adams' Sanger Institute lab that did not express the IFITM3 gene.

When mice with or without IFITM3 expression were infected with an influenza A H3N2 strain or the H1N1 2009 strain, the team found that the animals lacking IFITM3 were far more predisposed to severe infections that shared symptoms and features with those seen in humans with the most serious influenza cases.

"When you infect these mice that are missing the IFITM3 gene with influenza, then the mice display all of the symptoms of a severe influenza respiratory and lung infection," Kellam said.

The mouse model findings fit with past studies demonstrating that IFITM3's gene product not only prevents viruses from getting out of the endosome packages that they use to infiltrate host cells but also flags them for destruction by the cell.

"It stops the viruses from getting into the cells — either human cells or mouse cells — in the laboratory. And that block seems to be a really key defense in terms of a strategy, because the mice do really poorly without it," co-corresponding author Abraham Brass, a researcher affiliated with the Ragon Institute and the Massachusetts General Hospital, explained during the conference call.

"If the viruses get into a cell they multiply exponentially," he added. "So stopping viruses early can be a huge advantage … that takes a big burden off the immune system."

From these findings, the researchers speculated that when IFITM3 is not fully functional, the immune system might be forced to cope with a much larger viral load, upping the chances of severe infection. Once they are let loose in host cells, viruses also have the chance to tinker with immune system components that help recognize viruses, Brass noted.

When the researchers sequenced almost 2,000 bases from the IFITM3 locus from blood samples collected for 53 patients hospitalized with H1N1/09 flu in British and Scottish hospitals, they found that 13 percent carried at least one known variant in the gene.

Moreover, some 6 percent of the hospitalized patients had the same variant in IFITM3 — a SNP called rs12252 that's predicted to code for a protein product that's less capable of blocking flu virus infection. In contrast, the same variant is found in just one in every 400 people with European ancestry overall, based on available population data, study authors explained.

Though the gene is likely only one part of a complex genetic network that influences susceptibility to infection, the team believes it will be worth exploring the consequences of IFITM3 gene variation in many more individuals, including those from other populations.

"It's wonderful to have found a gene defect which is very specific that can account for a significant proportion of those that became seriously ill," co-author Peter Openshaw, director of Imperial College London's Centre for Respiratory Infection, told reporters. "It's a really important part of the jigsaw that we're trying to assemble to account for the variability and susceptibility to disease."

Once they have a better idea of the predictive information provided by looking at IFITM3, the researchers said it might ultimately be possible to boost its activity in vulnerable individuals or to use existing flu prevention measures such as vaccination or antiviral treatment to help prevent flu in those at highest of risk of severe infection.

Because there are concerns over the spread of flu viruses in animal populations, the study's authors explained, there is also some thought of augmenting IFITM3 activity in pigs, birds, or other animals through selective breeding to rein in their propensity for developing serious flu infections.

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