Swine flu variant linked to fatal cases may have disabled the clearing mechanism

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http://www.wellcome.ac.uk/News/2010/News/WTX063206.htm

Swine flu variant linked to fatal cases may have disabled the clearing mechanism

of lungs

25 October 2010

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, published in the `Journal of Virology' and part-funded by the

Wellcome Trust, suggests that the mutant virus could have impaired the lungs'

ability to clear out germs and highlights the potential for deadlier strains of

flu to emerge and spread.

Although the 2009 pandemic of H1N1 influenza caused thousands of deaths

worldwide, the majority of cases were relatively mild. A variant of the virus

carried a mutation termed D222G in a protein called haemagglutinin (the 'H' of

H1N1) on the surface of the virus. People infected with this variant were more

likely to have severe and fatal illness. According to a World Health

Organization report, the D222G mutation was found in fewer than two in every 100

cases of 2009 pandemic flu, but was responsible for around seven in every 100

deaths.

Viruses 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 up towards 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

collaborating researchers at the University of Marburg, Germany. 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, "

explains Professor Ten Feizi from 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 on 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. "

The study builds on earlier work by Professor Feizi and 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.

Reference

Liu Y et al. Altered receptor specificity and cell tropism of D222G

haemagglutinin mutants from fatal cases of pandemic A(H1N1) 2009 influenza.

Journal of Virology 2010; 84(22).