Innate Susceptibility to Norovirus Infections Influenced by FUT2 Genotype in a United States Pediatric Population

(See the Editorial Commentary by Debbink on pages 1639–41.) Norovirus is associated with nearly one-fifth of acute gastroenteritis (AGE) cases worldwide and is the leading cause of pediatric AGE in countries with universal rotavirus vaccination [1, 2]. Norovirus causes 200 000 pediatric deaths each year in developing countries [3]. Though rarely fatal in developed countries, norovirus AGE causes substantial morbidity and is responsible for 20 million cases annually in the United States alone [4]. The illness is characterized by sudden onset of severe vomiting and dehydrating diarrhea lasting 1–3 days [5]. Its high transmissibility makes norovirus an important public health concern, particularly in closed settings such as long-term care facilities, schools and child care centers, and military barracks [5, 6]. Human susceptibility to norovirus infection is thought to be at least partially dependent upon an individual's fucosyltransferase 2 (FUT2) genotype [7–16]. FUT2 controls the secretion of ABO histo-blood group antigens (HBGAs) at the gut surface. These carbohydrates serve as binding ligands and presumed receptors for caliciviruses, the virus family that includes norovirus [7]. However, in vitro and in silico studies have shown that noroviruses bind to HBGAs in a strain-specific manner [8, 9]. At least 1 functional FUT2 allele is present in 70%–80% of individuals, who are referred to as FUT2 “secretors” [17]. FUT2 is inactivated in the remaining 20%–30% (“nonsecretors”) by homozygous 428G > A nonsense mutations in European and African populations, or less common variants such as the 385A > T missense mutation found in Asian populations [17]. Individuals of Meso-American descent rarely carry these inactivating mutations [10, 17]. In challenge studies, FUT2 nonsecretors have demonstrated resistance to specific noroviruses, developing neither symptoms nor antibody response to norovirus genotypes GI.1 or GII.4 [11, 12, 18]. In epidemiologic studies, FUT2 nonsecretors have demonstrated significantly lower susceptibility to symptomatic infection by some norovirus genotypes (GI.1, GII.3, GII.4) [13–15, 18] but not others (GI.3, GII.3) [15, 16]. Although numerous outbreak studies have shown increased susceptibility of FUT2 secretors to specific noroviruses, the impact of FUT2 on overall risk of sporadic norovirus in racially/ethnically diverse populations has not been examined. Furthermore, secretor genetics in relation to asymptomatic shedding of norovirus has not been studied in populations in which the nonsecretor genotype is common. Finally, although in vitro work suggests that A and B blood group antigens may modify risk of norovirus infection in secretor individuals [8], this question has not been well addressed in epidemiologic studies. With norovirus vaccines currently in development [2], understanding population patterns of susceptibility to this pathogen is crucial. Our study utilizes a large, prospective, geographically diverse AGE surveillance network to identify sporadic pediatric norovirus infections. We use these surveillance data to determine the relationship of FUT2 secretor status to symptomatic and asymptomatic norovirus infection and modification of that relationship by non-O blood group types, and to describe FUT2 secretor status in the United States by racial/ethnic background.