05:04am Sunday 24 September 2017

Gene can turn flu into a killer

Adapted from a news release issued by the Wellcome Trust Sanger Institute

A genetic finding could help explain why influenza becomes a life-threatening disease in some people while it has only mild effects in others. New research by a consortium of UK and US scientists, published in the journal Nature, has identified for the first time a human gene that influences how we respond to influenza infection.

People who carry a particular variant of a gene called IFITM3, which encodes a protein of the same name, are significantly more likely to be hospitalised when they fall ill with influenza than those who carry other variants, the team found. This gene plays a critical role in protecting the body against infection with influenza and a rare version of it appears to make people more susceptible to severe forms of the disease.

Clinical samples for the study were provided by the MOSAIC consortium in England and Scotland, co-ordinated from the Centre for Respiratory Infection (CRI) at Imperial College London, and the GenISIS consortium in Scotland. These were pivotal for the human genetics component of the work.

“This new discovery is the first clue from our detailed study of the devastating effects of flu in hospitalised patients”, said study co-author Professor Peter Openshaw, Director of the CRI in the National Heart and Lung Institute at Imperial. “It vindicates our conviction that there is something unusual about these patients, and that ground-breaking clinical studies can be performed in the UK”.

A central question about viruses is why some people suffer badly from an infection and others do not. IFITM3 is an important protein that protects cells against virus infection and is thought to play a critical role in the immune system’s response against such viruses as H1N1 pandemic influenza, commonly known as swine flu. When the protein is present in large quantities, the spread of the virus in lungs is hindered, but if the protein is defective or absent, the virus can spread more easily, causing severe disease.

“Although this protein is extremely important in limiting the spread of viruses in cells, little is known about how it works in lungs,” explains Aaron Everitt, first author from the Wellcome Trust Sanger Institute. “Our research plays a fundamental part in explaining how both the gene and protein are linked to viral susceptibility.”

The antiviral role of IFITM3 in humans was first suggested by studies using a genetic screen, which showed that the protein blocked the growth of influenza virus and dengue virus in cells. This led the team to ask whether IFITM3 protected mice from viral infections. They removed the IFITM3 gene in mice and found that once they contracted influenza, the symptoms became much more severe compared to mice with IFITM3. In effect, they found the loss of this single gene in mice can turn a mild case of influenza into a fatal infection.

The researchers then sequenced the IFITM3 genes of 53 patients hospitalised with influenza and found that some have a genetic mutant form of IFITM3, which is rare in normal people. This variant gene encodes a shortened version of the protein, which makes cells more susceptible to viral infection.

The research was supported by the Wellcome Trust. The MOSAIC work was supported by Imperial’s National Institute for Health Research Comprehensive Biomedical Research Centre (cBRC), the Wellcome Trust and the Medical Research Council.

Journal reference

Everitt et al ‘IFITM3 restricts the morbidity and mortality associated with influenza’ Nature, published online 25 March 2012. doi:10.1038/nature10921

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