A Homozygous Nonsense Mutation (428G→A) in the Human Secretor ( FUT2 ) Gene Provides Resistance to Symptomatic Norovirus (GGII) Infections

Abstract

Noroviruses (formerly Norwalk-like viruses) are a major cause of acute gastroenteritis worldwide and are associated with a significant number of nosocomial and food-borne outbreaks. In this study we show that the human secretor FUT2 gene, which codes for an ␣(1,2)-fucosyltransferase synthesizing the H-type 1 antigen in saliva and mucosa, is associated with susceptibility to norovirus infections. Allelic polymorphism characterization at nucleotide 428 for symptomatic (n ‫؍‬ 53) and asymptomatic (n ‫؍‬ 62) individuals associated with nosocomial and sporadic norovirus outbreaks revealed that homozygous nonsense mutation (428G3A) in FUT2 segregated with complete resistance for the disease. Of all symptomatic individuals, 49% were homozygous (SeSe) and 51% heterozygous (Sese 428 ) secretors, and none were secretor negative (se 428 se 428 ), in contrast to 20% nonsecretors (se 428 se 428 ) among Swedish blood donors (n ‫؍‬ 104) (P < 0.0002) and 29% for asymptomatic individuals associated with nosocomial outbreaks (P < 0.00001). Furthermore, saliva from secretorpositive and symptomatic patients but not from secretor-negative and asymptomatic individuals bound the norovirus strain responsible for that particular outbreak. This is the first report showing that the FUT2 nonsecretor (se 428 se 428 ) genotype is associated with resistance to nosocomial and sporadic outbreaks with norovirus.Noroviruses are the major cause of acute gastroenteritis worldwide among adults and are associated with the illness "winter vomiting disease," characterized by a short incubation period (24 to 48 h) and significant vomiting and diarrhea. While the viruses are highly contagious, with attack rates up to 70% (12), volunteer challenge studies have shown that a subset of individuals remain uninfected even after repeated challenges (2,20,26). At present, it is not clear why a fraction of individuals remain uninfected in norovirus outbreaks and why some volunteers are repeatedly resistant to experimental Norwalk virus inoculations. Recently, it was suggested that histo-blood group antigens and the secretor status might be associated with experimental Norwalk virus infections (4,10,11,16,17).The FUT2 gene, which is responsible for the secretor phenotype, encodes an ␣(1,2)-fucosyltransferase that regulates the expression of the ABH antigens in saliva and mucosal tissues and secretions. The FUT2 gene has a significant polymorphism with typical ethnic specificity (13). The nonsense mutation 428G3A (Trp1433stop) is characteristic for the dominating nonsecretor allele (se 428 ) in Europeans and appears in about 20% of the Caucasian population (13).The facts that about 20% of Europeans are nonsecretors and norovirus attack rates seldom exceeds 80% in a given outbreak led us to investigate, throughout a series of prospective studies, if the FUT2 secretor gene was associated with resistance to nosocomial and sporadic outbreaks caused by genogroup II (GGII) noroviruses, which dominate in all parts of the world (14). MATERIALS AND METHODSSubjects and sampl...

Evolution of microparasites in spatially and genetically structured host populations: The example of RHDV infecting rabbits

“…It has been demonstrated that some strains are able to infect only secretors while others are expected to infect non-secretors only (Le Pendu et al, 2006;Tan and Jiang, 2005). In parallel, field studies on authentic outbreaks conducted in Sweden revealed that all the strains recorded infected secretors only, leading the authors to wonder if non-secretors were resistant to all noroviruses (Thorven et al, 2005). Here we propose another scenario.…”

Quasispecies dynamics and molecular evolution of human norovirus capsid P region during chronic infection

“…The most reasonable explanation for our different observations is that we investigated evolutionarily conserved motifs in the capsid of a chronically infected individual with constant ABO, Lewis and secretor status, properties that affect NoV susceptibility (Le Pendu et al, 2006;Lindesmith et al, 2003;Thorven et al, 2005). In contrast, Chackravarty and coworkers investigated conserved motifs among different strains from different individuals, presumably also different ethnic groups, each with unique immunity and HBGA properties.…”

Human genetics of infectious diseases: between proof of principle and paradigm

“…The situation may be even more complicated, as homozygosity for the CCR5 Δ32 allele was recently reported to be associated with symptomatic West Nile virus infection (70), indicating that selective pressure may also be negative, depending on the microbial environment. Finally, a single nonsense FUT2 mutation, G428A, is the most common mutation responsible for the Se -phenotype in populations of European and African descent, representing more than 95% of the European null FUT2 alleles (59,71). It remains unclear whether the recurrence of this mutation is due to a hot spot and/or a founder effect under positive selective pressure.…”

“…Finally, resistance to noroviruses (also known as Norwalk-like viruses), a leading cause of gastroenteritis, was recently shown to be associated with mutations in the fucosyltransferase 2 (FUT2) gene (56), which encodes an α(1,2)-fucosyltransferase that regulates the expression of ABH histo-blood group antigens on the surface of epithelial cells and in mucosal secretions (57). Several inactivating FUT2 mutations are responsible for the nonsecretor phenotype (Se -) characterized by a lack of expression of norovirus coreceptors, ABH antigens, on epithelial cells and complete resistance to symptomatic norovirus infection in experimental and natural conditions (58,59). It is thus clear that infectious diseases caused by these four common pathogens result from autosomal dominant susceptibility.…”