Monday, March 02, 2015

EID Journal: Emergence of D225G Variant A/H1N1, 2013–14 Flu Season, Florida

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Flu Virus binding to Receptor Cells – Credit CDC

 

# 9775

 

Although we’ve barely seen any A/H1N1 infections in North America during this latest flu season – last year was a different story, with H1N1 dominating  the flu scene. 

 

Today’s EID Journal carries a dispatch describing the detection of a small number of unusually severe H1N1 cases in Florida last year, which they have linked to the emergence of a D225G mutation that increased the virus’s ability to bind deep into the lungs.

 

If this sounds vaguely familiar, it is because we’ve been down this road before during the H1N1 pandemic. Since we have a bit of history with this variant, a quick review:

 

In November 2009 the Norwegian Institute of Public Health (see Norway Reports An H1N1 Mutation) announced the discovery of a mutation that “could possibly make the virus more prone to infect deeper in the airways and thus cause more severe disease."

Word of the `Norway’ or D222G (D225G in influenza H3 Numbering) mutation immediately sent researchers around the world on a hunt for similar changes in the virus, and over the following months several variations on a theme were discovered; D222N, D222E, and D222A.

 

The D222G mutation involves a single amino acid change in the HA1 gene at position 222 from aspartic acid (D) to glycine (G).

The pdmH1N1 virus carrying this mutation appeared to bind more readily to receptor cells (α2-3) found deep 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.

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(A Very Simplified Illustration of RBDs)

Like a key into a padlock, the RBD must `fit’ in order to open the cell to infection.

Similarly, D222A changes the HA1 gene at position 222 to Alanine, while D222E changes the gene to Glutamic acid and D222N changes to Asparagine.

This D222G mutation had actually been detected months earlier, and in several other countries, but Norway was the first country to announce a possible link between that mutation and greater virulence.

 

While a worrisome genetic change, it appeared that it was a fairly rare variant. 

 

In January of 2010, the World Health Organization’s Weekly Epidemiological Record (No. 4, 2010, 85, 21–28) provided a detailed overview of what was then known about this mutation.  While stating that more study was needed, the WHO pointed out:

  • The overall prevalence of D222G was <1.8% (52 detections among >2755 HA sequences) in contrast to a rate of 7.1% in fatal cases.
  • They reported on the occurrence of  two other mutations at this amino acid position, D222E and D222N, although their significance is unclear.
  • And concluded `Based on currently available virological, epidemiological and clinical information, the D222G substitution does not appear to pose a major public health issue.’

 

The debate over the significance (and origins) of the D222G mutation have continued since then. You can revisit some of those studies in the following blogs:

 

Eurosurveillance: Analysis Of Fatal H1N1 Cases In The UK)

Eurosurveillance: Debating The D222G/N Mutation In H1N1

D222G And Deep Lung Infections

 

In 2013, in EuroSurveillance: Revisiting The D222G Mutation In A/H1N1pdm09, we saw a study that suggested viruses with this mutation don’t transmit well in the wild, and that most of the time this variant comes about through a spontaneous mutation in the host after the host has been infected.  

 

The concern is that viruses can change, and co-mutations could occur that could make the D222G mutation more transmissible.

 

Fast forward to today’s EID report, and we learn of the discovery of the D224G mutation in a small number of unusually severe flu cases in Florida last year.

 

Volume 21, Number 4—April 2015
Dispatch

Severity of Influenza A(H1N1) Illness and Emergence of D225G Variant, 2013–14 Influenza Season, Florida, USA

Nicole M. IovineComments to Author , J. Glenn Morris, Kristianna Fredenburg, Kenneth Rand, Hassan Alnuaimat, Gloria Lipori, Joseph Brew, and John A. Lednicky

Author affiliations: University of Florida, Gainesville, Florida, USA (N.M. Iovine, J.G. Morris Jr., K. Fredenburg, K. Rand, H. Alnuaimat, G. Lipori, J.A. Lednicky); Florida Department of Health, Gainesville (J. Brew)

 

Abstract

Despite a regional decline in influenza A(H1N1)pdm09 virus infections during 2013–14, cases at a Florida hospital were more severe than those during 2009–10. Examined strains had a hemagglutinin polymorphism associated with enhanced binding to lower respiratory tract receptors. Genetic changes in this virus must be monitored to predict the effect of future pandemic viruses.

<SNIP >

The molecular basis for the ability of the H1N1 viruses to cause severe lower respiratory tract disease was first noted with the 1918 pandemic H1N1 virus (10). A single amino acid change of aspartic acid at position 225 to glycine (D225G) enabled binding to α2-3- and α2-6-sialylglycans (10,11). The association of this polymorphism with severe and lower respiratory tract disease was also noted with the A(H1N1)pdm09 virus from small subsets of patients during the 2009–10 influenza season (1214). To determine if this polymorphism existed in the H1N1 viruses isolated in our study, we sequenced viral RNA corresponding to the coding regions of all 8 influenza virus genomic segments from viruses isolated from or detected in 7 patient samples (GenBank sequences KJ645758–KJ645765 and KJ645774–KJ645791) (8). The consensus sequences were similar to those of key American A(H1N1)pdm09 virus isolates, and like a subset of those isolates, our 7 H1N1 isolates harbored the D225G polymorphism.

None of the 7 isolates harbored the H275Y neuraminidase polymorphism that confers oseltamivir resistance (15), and in vitro test results confirmed oseltamivir susceptibility (data not shown). To determine whether polymorphisms in the 3′ and 5′ untranslated regions were associated with the 2013 H1N1 virus, we sequenced 1 isolate by using rapid amplification of cDNA ends (FirstChoice RLM-RACE; Ambion, Bleiswijk, the Netherlands). No substantial differences were detected between this virus and the original A(H1N1)pdm09 virus or circulating contemporary H1N1 viruses.

Our work was subject to certain limitations. First, the use of ICD-9 codes for diagnostic information is imprecise. To mitigate this, we considered only 2 ICD-9 codes for influenza. Second, it is not known whether our findings extend beyond our region. Last, changes in health-seeking behavior in 2009–10 versus 2013–14 were not addressed.

Conclusions

We hypothesize that the emergence of an influenza virus variant bearing the D225G polymorphism enabled the 2013 H1N1 virus to infect lower and upper respiratory tract cells, thereby contributing to the increased severity of the 2013–14 influenza season in our region. Our findings highlight the importance of monitoring genetic changes in the 2013 H1N1 virus to predict the effect of future influenza viruses.

 

As we’ve discussed before (see When Influenza Goes Rogue & CHP CDW Report On Antiviral Resistant Influenza In Hong Kong), even seasonal influenza needs to be watched carefully, as it is capable of dramatically changing its behavior should it pick up the right mutations. 

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