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doi: 10.1371/journal.pone.0005593. Epub 2009 May 18.

The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection

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The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection

Beatrice Carlsson et al. PLoS One.2009.

Abstract

In November 2004, 116 individuals in an elderly nursing home in El Grao de Castellón, Spain were symptomatically infected with genogroup II.4 (GII.4) norovirus. The global attack rate was 54.2%. Genotyping of 34 symptomatic individuals regarding the FUT2 gene revealed that one patient was, surprisingly, a non-secretor, hence indicating secretor-independent infection. Lewis genotyping revealed that Lewis-positive and negative individuals were susceptible to symptomatic norovirus infection indicating that Lewis status did not predict susceptibility. Saliva based ELISA assays were used to determine binding of the outbreak virus to saliva samples. Saliva from a secretor-negative individual bound the authentic outbreak GII.4 Valencia/2004/Es virus, but did not in contrast to secretor-positive saliva bind VLP of other strains including the GII.4 Dijon strain. Amino acid comparison of antigenic A and B sites located on the external loops of the P2 domain revealed distinct differences between the Valencia/2004/Es and Dijon strains. All three aa in each antigenic site as well as 10/11 recently identified evolutionary hot spots, were unique in the Valencia/2004/Es strain compared to the Dijon strain. To the best of our knowledge, this is the first example of symptomatic GII.4 norovirus infection of a Le(a+b-) individual homozygous for the G428A nonsense mutation in FUT2. Taken together, our study provides new insights into the host genetic susceptibility to norovirus infections and evolution of the globally dominating GII.4 viruses.

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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 analysis of the outbreak Valencia/2004/Es strain.
A) Phylogenetic tree of the NoV RNA polymerase gene (region A in ORF1) from the outbreak (Valencia/2004/Es) and reference strains, obtained from the European Food-borne viruses database . The phylogenetic tree was constructed using the UPGMA clustering method with distance calculation using the Jukes-Cantor correction for evolutionary rate by Molecular Evolutionaty Genetics Analysis (MEGA version 2.1). B) Phylogenetic tree of the outbreak (Valencia/2004/Es) capsid P2 domain (aa 279 to 405) and selected reference strains. The phylogenetic tree was constructed using the UPGMA clustering method with distance calculation using the Poisson correction for evolutionary rate by Molecular Evolutionaty Genetics Analysis (MEGA version 4.1).
Figure 2
Figure 2. Binding of authentic Valencia/2004/Es virus to saliva.
Binding of saliva from secretors and non-secretors to the GII.4 outbreak virus. Dotted line represents cut-off value. Cut-off value (0.380) was three times the mean OD450 of three known negative control samples. The box shows interquartile range; the range between the first and third quartiles. Median is marked as a horizontal line within the box. Whiskers represent samples not more than 1.5 times the box width away from the box. The ring represents a sample within 1.5–3 box lengths from upper or lower edge of the box and the asterisk marks an extreme case (a value more than 3 box (lenghts from the edge of the box), here representing patient B (asymptomatic non-secretor).
Figure 3
Figure 3. Detection of histo-blood group antigens and VLP binding to saliva from patient A and B.
A) ABO and Lewis histo-blood group phenotyping of saliva samples from the non-secretor patients A and B confirms a Lea+b− phenotype. Saliva samples were coated in microtiter wells and incubated with aA (anti A), aB, aLea or aLeb antibodies separately. The limit of detection for each antibody has been subtracted from each bar. Both patients reacted strongly only with the aLea antibody and not with the aLeb, aA or aB antibodies and were thereby classified as Lea+b−. A, AB or O denotes blood groups, Le or le denotes Lewis positive or Lewis negative, respectively, and Se or se denotes secretors or non-secretors. B) Saliva from non-secretor patients A and B or non-secretor controls do not bind Chron, Dijon or Norwalk VLPs whereas saliva from secretors bind all three strains.
Figure 4
Figure 4. Comparison of antigenic sites between the outbreak Valencia/2004/Es and Dijon strain.
The outbreak Valencia/2004/Es strain have distinct amino acids in antigenic A and B regions of the P2 domain compared to the Dijon strain. Amino acid alignment (Clustal W 1.8 with default parameters on the European Bioinformatics Institute server) of partial capsid protein (aa 241 to 419) of the Dijon171/96 [AF472623] and the outbreak Valencia/2004/Es strains. The Valencia/2004/Es sequences, are obtained from three randomly chosen patients (no 207, 208 and 225). The aa constituting the P2 domain (aa 279 to 405) are shaded in light grey. Antigenic site A (aa 296–298) and site B (393–395) proposed by Allen et al. are indicated. The Valencia/2004/Es has a TQN and a STT motif in the A and B site, while the Dijon strain have a SHD motif in site A and a –NN motif in site B. Besides from the A and B site, 11 additional substitutions (marked number 1 to 11) were found when comparing the capsid P2 domain of Valencia and Dijon, 10 out of these 11 (number 2 to 11) correlated with evolutional hot spots (highlighted by dark grey) identified by Allen and coworkers .
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