Swine flu variant linked to fatal cases might have disabled the clearing mechanism of lungs

A variant of last year’s pandemic influenza linked to fatal cases carried a mutation that enabled it to infect a different subset of cells lining the airway, according to new research. The study, due to be published next week in the Journal of Virology, suggests that the mutant virus could have impaired the lungs’ ability to clear out germs. The researchers behind the study, from Imperial College London, the Medical Research Council National Institute for Medical Research and the University of Marburg said the findings highlight the potential for deadlier strains of flu to emerge and spread.

The 2009 pandemic of H1N1 influenza caused thousands of deaths worldwide, but the majority of cases were relatively mild. A variant of the virus carried a mutation termed D222G in a protein on the surface of the virus, and people infected with this variant were more likely to have severe and fatal illness. According to a World Health Organisation report, the D222G mutation was found in less than two in every hundred cases of 2009 pandemic flu, but was responsible for around seven in every hundred deaths.

iruses infect cells by attaching to receptor molecules on the cell surface. Different receptors are present on different cell types, and a virus can only infect cells that have the right receptors for the protein on its own surface.

The new research shows that flu virus with the D222G mutation can bind to a broader range of receptors in the airway, including receptors that are present on cells called ciliated cells. These cells, found in the lining of the airway, have hair-like projections called cilia. The cilia sway back and forth to move mucus with trapped particles upward toward the mouth, and this is normally swallowed or coughed up. When ciliated cells become infected, the cilia stop moving and this vital clearance function is impaired. Inhaled viruses and bacteria can then reach the lung more easily, where they can potentially cause pneumonia.

The mutant virus has an increased capacity to infect ciliated cells, as shown by the collaborating group at the University of Marburg. Infection of the ciliated cells would sabotage the lungs’ clearing mechanism and could be one factor that made the D222G mutation more virulent, the researchers suggest.

“This simple mutation, which swapped one building block of a virus protein for another, apparently resulted in a more virulent version of the H1N1 virus,” said Professor Ten Feizi from the Department of Medicine at Imperial College London, who led the study. “We think this is at least partly due to the virus being able to bind to different receptors, which allowed it to infect ciliated cells and stop them from clearing out germs.

“If the mutant virus were to acquire the ability to spread more widely, the consequences could be very serious. The study goes to show how important it is that the WHO Global Influenza Surveillance Network continues to monitor closely the emergence of new variants of the flu virus. Even though the 2009 pandemic was relatively mild, it’s vital that we handle outbreaks cautiously and stay vigilant. The virus is constantly evolving, and it’s possible that a new form as dangerous as the 1918 pandemic could emerge.”

Professor Feizi and her team study the receptor specificity of different flu viruses by attaching onto a glass surface a range of different carbohydrates, resembling the receptors present on the surface of airway lining cells. The virus is then incubated on top of the glass surface, and using a fluorescent dye, the researchers can see the receptors on the plate to which the virus binds.

The study builds on earlier work by Professor Feizi and her colleagues which showed that compared with seasonal influenza, the 2009 pandemic virus could bind to a broader range of receptor types. The previous study showed that pandemic flu had some affinity for so-called alpha2-3 receptors, as well as the alpha2-6 receptors favoured by seasonal flu. Now they have shown that this affinity for alpha2-3 receptors is substantially enhanced in cases of pandemic flu with the D222G mutation. Whereas alpha2-6 receptors are found in the nose, throat and upper airway, alpha2-3 receptors are prevalent in the lung but also on ciliated cells throughout the respiratory system.

The study was funded by the Wellcome Trust, the Medical Research Council, Biotechnology and Biological Sciences Research Council, the UK Research Councils’ Basic Technology Initiative, EPSRC’s Follow-on Translational grant, and German grants from the Von Behring-Roentgen Foundation and LOEWE Program UGMLC of the State of Hesse.

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Notes to editors:

1. Journal reference: Y. Liu et al. “Altered receptor specificity and cell tropism of D222G haemagglutinin mutants from fatal cases of pandemic A(H1N1) 2009 influenza.” Journal of Virology, November 2010, Volume 84, Issue 22.

A copy of the paper can be downloaded here: https://fileexchange.imperial.ac.uk/files/0be92a21af5/Liu%20et%20al%20H1N1pdm%20paper%20J%20%20virol.pdf

2. In the D222G mutant virus, there is an amino acid substitution in position 222 of the haemagglutinin molecule: asparagine is replaced with glycine.

3. The overall prevalence of the D222G mutation is recorded as less than 1.8 per cent of total cases of pandemic influenza A(H1N1), compared with 7.1 per cent of fatal cases. Source: “Preliminary review of D222G amino acid substitution in the haemagglutinin of pandemic influenza A (H1N1) 2009 viruses.” World Health Organisation, 28 December 2009.

4. About Imperial College London

Consistently rated amongst the world’s best universities, Imperial College London is a science-based institution with a reputation for excellence in teaching and research that attracts 14,000 students and 6,000 staff of the highest international quality. Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that improve quality of life and the environment – underpinned by a dynamic enterprise culture.

Since its foundation in 1907, Imperial’s contributions to society have included the discovery of penicillin, the development of holography and the foundations of fibre optics. This commitment to the application of research for the benefit of all continues today, with current focuses including interdisciplinary collaborations to improve global health, tackle climate change, develop sustainable sources of energy and address security challenges.

In 2007, Imperial College London and Imperial College Healthcare NHS Trust formed the UK’s first Academic Health Science Centre. This unique partnership aims to improve the quality of life of patients and populations by taking new discoveries and translating them into new therapies as quickly as possible.

Website: www.imperial.ac.uk

5. About the Wellcome Trust

The Wellcome Trust is a global charity dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust’s breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests.

Website: www.wellcome.ac.uk

6. About the Medical Research Council

For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century.

Website: www.mrc.ac.uk

7. About the Engineering and Physical Sciences Research Council

The Engineering and Physical Sciences Research Council (EPSRC) is the UK’s main agency for funding research in engineering and the physical sciences. The EPSRC invests around £800 million a year in research and postgraduate training, to help the nation handle the next generation of technological change.

Website: www.epsrc.ac.uk

8. About BBSRC

The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £470 million in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, healthcare and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes.

The Babraham Institute, Institute for Animal Health, Institute of Food Research, John Innes Centre and Rothamsted Research are Institutes of BBSRC. The Institutes conduct long-term, mission-oriented research using specialist facilities. They have strong interactions with industry, Government departments and other end-users of their research.

Website: http://www.bbsrc.ac.uk

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