Gene Explains Why Flu Can Be Serious

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Academic Journal
Main Category: Genetics
Also Included In: Flu / Cold / SARS;  Swine Flu
Article Date: 26 Mar 2012 - 3:00 PST


People with a rare variant of a gene that codes for an anti-viral protein are more likely to end up in hospital seriously ill when they get the flu than others who carry other variants, according to new research led by the Wellcome Trust Sanger Institute in the UK that was published in Nature on Sunday.

People who do not have the rare variant of IFITM3 only have mild reactions to the influenza virus, said the researchers who found the gene codes for a protein that is important for helping the body defend itself against the virus.

It appears that when there is plenty of IFITM3 protein in the body, the flu virus can't penetrate deep into the lungs.

The 2009 H1N1 "swine flu" pandemic showed how quickly a new virus can spread, and how a generally mild infection can become serious and even kill a small subset of the population, the authors write in their background information.

The antiviral role of IFITM3 in humans was first suggested by studies that showed the protein blocked the growth of influenza virus and dengue virus in cultured cells.

So they decided to take this further by examining the effect of this protein family in lab mice.

To do this they used "knock out" models of mice, that is mice that have certain genes silenced or knocked out.

Doing this for the IFITM genes, they found that "IFITM3 is essential for defending the host against influenza".

They found the lack of IFITM3 in mice can turn a mild case of flu into a fatal infection.

"Mice lacking Ifitm3 display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 'Spanish' influenza," they write.

Going back to testing the effect on cells in test tubes, they found lack of IFITM3 allowed a similar increased replication of the virus, and when they re-introduced IFITM3, it prevented it.

The researchers then tested the role of the gene in human infection. Examining sequences of IFITM3 genes of 53 patients hospitalized with influenza, they found some have a rare mutant form that affects the gene's ability to make the protein, or enough of it.

"We find that a statistically significant number of hospitalized subjects show enrichment for a minor IFITM3 allele (SNP rs12252 -C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro," they write.

Professor Paul Kellam, co-senior author from the Wellcome Trust Sanger Institute's Genome Campus in Hinxton, near Cambridge, told the media:

"Collectively, these data reveal that the action of a single antiviral protein, IFITM3, can profoundly alter the course of the flu and potentially other viruses in both human and mouse."

"To fully understand how both the protein and gene control our susceptibility to viral infections, we need to study the mechanisms of the gene variant more closely," he added.

First author Aaron Everitt, also from the Wellcome Trust's Genome Campus, said:

"Although this protein is extremely important in limiting the spread of viruses in cells, little is known about how it works in lungs."

"Our research plays a fundamental part in explaining how both the gene and protein are linked to viral susceptibility," he added.

Co-senior author Dr. Abraham Brass is Assistant Professor at the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, and also of the Gastrointestinal Unit of Massachusetts General Hospital. He said:

"Since IFITM3 appears to be a first line defender against infection, our efforts suggest that individuals and populations with less IFITM3 activity may be at increased risk during a pandemic and that IFITM3 could be vital for defending human populations against other viruses such as avian influenza virus and dengue virus."

Brass said as we learn more about the genetics of susceptibility to different viruses, the more possible it becomes for people to take informed precautions, such as getting vaccinated.

Written by Catharine Paddock PhD
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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