The G428A Nonsense Mutation in FUT2 Provides Strong but Not Absolute Protection against Symptomatic GII.4 Norovirus Infection

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 Lea+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.

Characterization of Emerging GII.g/GII.12 Noroviruses from a Gastroenteritis Outbreak in the United States in 2010

“…A seroprevalence study using donated blood also revealed that the presence of IgG titers against GII.4 strain was type A/B/O independent but correlated with the secretor phenotype (37). In another report, symptomatic GII.4 infections were also strongly associated with the Se phenotype (10). Although all the individuals in the current outbreak were Se ϩ , it is hard to conclude that GII.12 infection is Se ϩ dependent without Se-negative (Se Ϫ ) individuals exposed to these GII.12 strains.…”

Comprehensive Analysis of a Norovirus-Associated Gastroenteritis Outbreak, from the Environment to the Consumer

“…Evidence accumulated over the past 6 years indicates that HBGAs serve as ligands for NoV infection (5,6,15,17,18,25,26,39). However some studies showed discrepant results concerning the effect of either the ABO or the secretor phenotype, raising questions about the importance of HBGAs in norovirus infections (10,12,31,32,37).…”

“…In humans, the pleiotropic interaction of alleles at three loci, FUT3, FUT2, and ABO, determines the Lewis, secretor, and ABO phenotypes, respectively (28). The evidence that has accumulated from volunteers studies and from the analysis of outbreaks indicates that binding to these carbohydrates is required for infection (5,6,15,17,18,25,39). Moreover, various human NoV strains that bind to HBGAs present distinct specificities for HBGAs (13,14,38).…”

Norovirus

“…Examples of infection in nonsecretors include ones due to norovirus GII.2 Snow Mountain (307), GII.4 (308,309), and GI.3 (310,311). In fact, combining the data from two GI.3 outbreaks, it can be calculated that 11 of 22 (50%) nonsecretors and 46 of 90 (51%) secretors were infected (310,311).…”