Gene Can Transform Mild Flu Into A Life-threatening Disease

An international team of researchers has discovered a human genetic flaw that could explain why influenza makes some people more sick than others.

Reporting in the journal Nature, British and American researchers, led by the Wellcome Trust Sanger Institute (WTSI) in the UK, said the variant of the IFITM3 gene was much more common in people hospitalized for the flu than in those who were able to fight the disease at home.

The researchers said this could explain why during the 2009/10 H1N1 “swine flu” pandemic most people had mild symptoms, while others got seriously ill and died. They said they scoured genetic databases covering thousands of people and found evidence that around one in 400 people may have the flawed genetic variant.

IFITM3 is an important protein that protects cells against infection and is believed to play a crucial role in the immune system´s response against viruses such as H1N1. When the protein is abundant in the body, the spread of the virus in the lungs is hindered, but if the protein is defective or absent, the virus can spread rapidly, causing greater illness and perhaps death.

Aaron Everitt, lead researcher from WTSI, said although the IFITM3 protein is known to play an important role in “limiting the spread of viruses in cells, little is known about how it works in lungs.” Our new research helps to explain “how both the gene and protein are linked to viral susceptibility,” he added.

The role of IFITM3 in humans was first suggested by studies using a genetic screen, which showed the protein blocked the growth of the flu and dengue in cells. This finding led the team to further investigate how the gene works in both humans and mice.

For the study, the researchers removed the gene from mice and found when they developed flu, their symptoms were much worse than the mice that still had the gene. They found that the loss of this single gene in mice can turn a mild case of influenza into a potentially fatal infection.

Armed with this knowledge, the researchers sequenced the IFITM3 genes of 53 patients hospitalized with the flu and found three (one in 18) have a genetic mutation of this gene, which is rare in normal people.

“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,” said Dr. Abraham Brass, an Assistant Professor at the Ragon Institute and Gastrointestinal Unit of Massachusetts General Hospital, and co-lead author of the study.

The team said these findings need to be replicated in bigger studies before they can positively rule that the IFITM3 gene mutation is the key factor for causing serious illness.

Study co-author Professor Paul Kellam, from WTSI, said: “At the moment, if someone is in a more vulnerable group because of co-morbidity [another health problem], they would be offered the flu vaccine.” But, he said, having this variant would not make any difference to how people were treated.”

“Our research is important for people who have this variant as we predict their immune defenses could be weakened to some virus infections,” said Kellam. “Ultimately as we learn more about the genetics of susceptibility to viruses, then people can take informed precautions, such as vaccination to prevent infection.”

“This new discovery is the first clue from our detailed study of the devastating effects of flu in hospitalized patients,” Professor Peter Openshaw, director of the Center for Respiratory Infection at Imperial College London, told BBC News. “It vindicates our conviction that there is something unusual about these patients.”

Sir Mark Walport, director of the WTSI, said: “During the recent swine flu pandemic, many people found it remarkable that the same virus could provoke only mild symptoms in most people, while, more rarely, threatening the lives of others”

“This discovery points to a piece of the explanation: genetic variations affect the way in which different people respond to infection,” Walport said. “This important research adds to a growing scientific understanding that genetic factors affect the course of disease in more than one way. Genetic variations in a virus can increase its virulence, but genetic variations in that virus’s host – us – matter greatly as well.”

In the future, this genetic discovery could help doctors screen patients to identify if they will be at an increased risk of being brought down by flu, allowing them to be selected for priority vaccination or preventative treatment during outbreaks, the researchers wrote, adding it could also help to develop new vaccines or medicines that can stave off potentially more dangerous viruses such as the bird flu.

“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,” Brass told Reuters.

Samples for this study were obtained from the MOSAIC consortium in England and Scotland, coordinated from the Center for Respiratory Infection at Imperial College London, and the GenISIS consortium in Scotland at the Roslin Institute of the University of Edinburgh. These were critical for the human genetics component of the work.

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