Host Genetic Resistance to Symptomatic Norovirus (GGII.4) Infections in Denmark

Abstract

A total of 61 individuals involved in five norovirus outbreaks in Denmark were genotyped at nucleotides 428 and 571 of the FUT2 gene, determining secretor status, i.e., the presence of ABH antigens in secretions and on mucosa. A strong correlation (P ‫؍‬ 0.003) was found between the secretor phenotype and symptomatic disease, extending previous knowledge and confirming that nonsense mutations in the FUT2 gene provide protection against symptomatic norovirus (GGII.4) infections.Volunteer studies have shown that a subset of individuals are not affected by vomiting and diarrhea after challenges with noroviruses (1,16,19), and this information, together with the fact that attack rates seldom exceed 70% (4), suggests that inherited factors act to prevent certain individuals from symptomatic norovirus disease. Indeed, experimental and volunteer studies have indicated a correlation between secretor status and susceptibility to Norwalk virus (genogroup I norovirus) infections (3,12,14). These observations were recently confirmed and extended to also include authentic outbreaks by genogroup II viruses (17), which is the clinically most common genogroup of norovirus (9). Current knowledge thus suggests that secretor status determined by polymorphisms in the FUT2 gene is strongly associated with resistance to norovirus infections (3,11,12,17). Further support for this hypothesis is also the fact that nonsecretor and Lewis a-positive individuals have significantly lower antibody prevalence and titer to norovirus GGII than secretor and Lewis b-positive individuals (10). The association between secretor status and norovirus susceptibility is not fully understood, but transfection of the FUT2 gene to nonpermissive cells has been shown to increase cell susceptibility to norovirus infection (14), suggesting that the H antigen or a related structure acts as a receptor for the virus.FUT2 encodes an ␣(1,2)fucosyltransferase, which adds a fucose molecule to the H-type 1 precursor, giving the H-type 1 antigen. H-type 1 can, in contrast to its precursor, work as a precursor for the A and B blood group antigens. FUT2 determines the secretor status, which is the presence or absence of blood group ABH antigens on mucosal surfaces and in secretions such as saliva (5). Individuals carrying the secretor genotypes (SeSe or Sese) secrete the H antigen with or without A and/or B antigens, while individuals of the nonsecretor genotype (sese) do not. The polymorphisms found in the FUT2 gene show high ethnic specificity (8, 13), with a nonsense mutation at nucleotide 428 associated with the Caucasian populations (5, 8) The majority of the positive samples (90%) were submitted from hospitals, representing at least 30 different hospitals and situated in all parts of Denmark. For detection of norovirus in stool samples, purified viral RNA was reverse transcribed and PCR amplified (RT-PCR kit; QIAGEN, Hilden, Germany) by using the primers JV12 and JV13 essentially as described earlier (17,18). The PCR products (285 bp after trimming of the primer se...

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

“…That was particularly clear when individuals of the non-A subgroup were considered, which indicated that the A blood group antigen, which can be expressed on the digestive epithelial cells of secretors only, may have been a protective factor in this particular outbreak. Thus, polymorphisms at both the FUT2 and the ABO loci controlled sensitivity to disease in this shellfish-related outbreak, confirming the importance of these polymorphisms in determining the susceptibility to NoV infection previously observed from either volunteer studies or community outbreaks (2,5,17,24,25). In this study, several strains (NoV, AiV, SaV) were detected either in stool samples or in shellfish.…”

“…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).…”

Heterotypic Humoral and Cellular Immune Responses following Norwalk Virus Infection

“…Individuals who do not encode a functional FUT2 enzyme have a secretor-negative phenotype, do not express ABH HBGAs on mucosal surfaces, and are resistant to NV infection. Outbreak investigations have confirmed the association between HBGA expression and norovirus infection for some GI and GII strains (37,39,43,49,89). It remains likely that enzymes other than FUT2 may function as norovirus susceptibility factors because secretor-negative individuals have low-level norovirus-reactive antibodies (49,52,53) and can become infected after challenge with a GII.2 strain (52); in addition, some norovirus strains bind to FUT2-independent HBGAs in vitro (35,54,79).…”

Strain-Dependent Norovirus Bioaccumulation in Oysters

“…HBGAs are complex glycans present on many cell types, including red blood cells and vascular endothelial cells, as well as some epithelial cells (intestinal, urogenital, and respiratory). Volunteer studies and outbreak analyses indicate that binding to these carbohydrates is required for infection, with many strains infecting only a subset of the population based on their HBGA expression (15,20,25,27,28,48,49).…”