# 5263
For well over a year there has been considerable debate among virologists, and other researchers, over the impact of an amino acid substitution seen in a small percentage of 2009 H1N1 samples.
The `Norway’ or D222G/N (D225G/N in influenza H3 Numbering) mutation was first linked to more severe disease by Norwegian Scientists in November 2009, although patients carrying these strains can have mild illness as well.
While we’ve covered this territory a number of times over the past year, a brief (and hopefully simple) review is in order. If you are up to speed on receptor binding, and the history of the D222G/N variant, feel free to skip the next section.
This mutation involves a single amino acid change in the HA1 gene at position 222 from aspartic acid (D) to glycine (G) (or asparagine (N)).
The pdmH1N1 virus carrying this mutation appears to bind more readily to receptor cells (α2-3) found deeper in the lungs, whereas unmutated seasonal flu strains bind preferentially to the (α2-6) receptor cells found in the upper airway.
A virus’s ability to bind to specific cells is controlled by its RBD or Receptor Binding Domain; an area of its genetic code that allows it to attach to, and infect, specific types of host cells.
(A Very Simplified Illustration of RBDs)
Like a key into a padlock, the RBD must `fit’ in order to open the cell to infection.
The evidence for the D222G/N amino acid substitution driving increased virulence has been mixed, with the World Health Organization, the CDC, and the HPA continuing to investigate.
During the first week of January, Eurosurveillance printed a study looking at fatal and non-fatal cases of influenza in the UK (see Eurosurveillance: Analysis Of Fatal H1N1 Cases In The UK).
Ellis et al. reported that almost all of the virus samples tested in fatal and non-fatal cases during the early wave of the 2010/11 influenza season showed aspartic acid (D) at position 222.
In other words, no `Norway’ mutation.
Today, Eurosurveillance published a letter from an Italian researcher who has found a high percentage of D222G/N mutations in severely ill patients (43%) – particularly when taking virus samples from the lower respiratory tract (lungs).
You can read the entire letter at the link below.
Eurosurveillance, Volume 16, Issue 4, 27 January 2011
Letters
F Baldanti
The point being, that if the UK researchers were only taking nasal (or upper respiratory) swabs, they might be missing some D222G/N mutations.
In a reply, the authors of the original study concede that in many cases, only upper respiratory swabs were available for this analysis, and that when possible, samples from the lower respiratory system would be useful.
Eurosurveillance, Volume 16, Issue 4, 27 January 2011
Letters
J Ellis , M Galiano, R Pebody, A Lackenby, CI Thompson, A Bermingham, E McLean, H Zhao, S Bolotin, O Dar, J M Watson, M Zambon
This scholarly debate isn’t over, of course. As Ellis et al. state in their reply:
The selection and emergence of the D222G mutation as a cause or consequence of more severe lower respiratory tract infection is still to be resolved.
Emergence of this mutant is likely to exacerbate severity of disease, but by itself, may be neither necessary nor sufficient to account for a severe disease outcome, which is invariably a balance between virus virulence factors and host immune response capability.
It will take more samples, more research, and more time to determine the truth in the matter.
And even if this mutation should eventually be linked to higher virulence, its ultimate impact on public health will ride on how just prevalent this D222G/N is among the H1N1 viruses in circulation.
Stay tuned. There’s a lot left for us to discover.
