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. 2012;7(3):e33166.
doi: 10.1371/journal.pone.0033166. Epub 2012 Mar 6.

Fatal cases of influenza A(H3N2) in children: insights from whole genome sequence analysis

Monica Galiano  1 , Benjamin F Johnson, Richard Myers, Joanna Ellis, Rod Daniels, Maria Zambon
Affiliations

Fatal cases of influenza A(H3N2) in children: insights from whole genome sequence analysis

Monica Galiano et al. PLoS One. 2012.

Abstract

During the Northern Hemisphere winter of 2003-2004 the emergence of a novel influenza antigenic variant, A/Fujian/411/2002-like(H3N2), was associated with an unusually high number of fatalities in children. Seventeen fatal cases in the UK were laboratory confirmed for Fujian/411-like viruses. To look for phylogenetic patterns and genetic markers that might be associated with increased virulence, sequencing and phylogenetic analysis of the whole genomes of 63 viruses isolated from fatal cases and non fatal "control" cases was undertaken. The analysis revealed the circulation of two main genetic groups, I and II, both of which contained viruses from fatal cases. No associated amino acid substitutions could be linked with an exclusive or higher occurrence in fatal cases. The Fujian/411-like viruses in genetic groups I and II completely displaced other A(H3N2) viruses, but they disappeared after 2004. This study shows that two A(H3N2) virus genotypes circulated exclusively during the winter of 2003-2004 in the UK and caused an unusually high number of deaths in children. Host factors related to immune state and differences in genetic background between patients may also play important roles in determining the outcome of an influenza infection.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Phylogenetic relationships of the concatenated main coding regions of influenza A(H3N2) viruses isolated in the UK during 2003–2004.
Sequences from reference viruses A/Panama/2007/99 and A/Fujian/411/2002 were included in the dendrograms. For the purposes of comparison, the dendrograms also included sequences from A/New York/38/2003, A/New York/11/2003, A/New York/32/2003, A/New York/199/2003 and A/New York/52/2004. All phylogenies were rooted using A/Panama/2007/99 as an outgroup. Branch lengths are drawn to scale. Viruses isolated from fatal cases are displayed in red type. Bootstrap values (>70%) are displayed on the nodes. Genetic groups I and II are indicated with brackets. Amino acid substitutions characterising these groups are annotated on the nodes.
Figure 2
Figure 2. Phylogenetic relationships of the main coding regions of PB2, PB1, PA & HA of influenza A(H3N2) viruses isolated in the UK during 2003–2004.
Details are similar to those described in Figure 1 footnote.
Figure 3
Figure 3. Phylogenetic relationships of the main coding regions of NP, NA, M & NS of influenza A(H3N2) viruses isolated in the UK during 2003–2004.
Details are similar to those described in Figure 1 footnote.
Figure 4
Figure 4. Phylogenetic relationships of partial sequences (nucleotides 346 to 866) of the HA1 coding fragment for A(H3N2) viruses isolated in 2003–2004 in the UK and worldwide.
Genetic groups where viruses from the UK clustered are highlighted in green (I) and red (II). Some branches were condensed for clarity purposes; adjacent legends indicate the country/region where the majority of viruses within a cluster were isolated and the number of viruses included. These clusters also included sporadic viruses from other countries which were not detailed. Sequences from reference viruses A/Panama/2007/99 and A/Fujian/411/2002 were included in the phylogeny. The ML phylogeny was rooted using A/Panama/2007/99 as an outgroup. Branch lengths are drawn to scale. Bootstrap values (>70%) are displayed on the nodes.
Figure 5
Figure 5. Phylogenetic relationships of partial sequences (nucleotides 346 to 866) of the HA1 coding fragment for A(H3N2) viruses isolated between 2002 and 2008 in the UK.
The annotated box indicates the reference colours for viruses isolated in different influenza seasons, between 2002–2003 and 2007–2008. Genetic groups I and II, within the Fujian/411 clade, are indicated with brackets. Viruses from fatal cases are highlighted with #. Sequences from reference viruses A/Panama/2007/99 and A/Fujian/411/2002 were included in the phylogeny. The ML tree was rooted using A/Panama/2007/99 as an outgroup. Branch lengths are drawn to scale. Bootstrap values (>50%) and signature amino acid substitutions seen in viruses from 2003–2004 and 2004–05 are annotated on the nodes.
Figure 6
Figure 6. Surface representation of the hemagglutinin hetero-trimer from a seasonal H3N2 strain .
Location of the amino acids substitutions marking the transition between Panama-like and Fujian-like viruses are highlighted in red; those changes which differentiate viruses isolated since 2004–2005 from Fujian/411-like viruses are coloured in blue; genetic group I-specific changes are highlighted in green and genetic group II-specific changes are marked with yellow.
See this image and copyright information in PMC

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