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

Abstract

Background: Norovirus is a leading cause of acute gastroenteritis (AGE). Noroviruses bind to gut histo-blood group antigens (HBGAs), but only 70%-80% of individuals have a functional copy of the FUT2 ("secretor") gene required for gut HBGA expression; these individuals are known as "secretors." Susceptibility to some noroviruses depends on FUT2 secretor status, but the population impact of this association is not established.

Methods: From December 2011 to November 2012, active AGE surveillance was performed at 6 geographically diverse pediatric sites in the United States. Case patients aged <5 years were recruited from emergency departments and inpatient units; age-matched healthy controls were recruited at well-child visits. Salivary DNA was collected to determine secretor status and genetic ancestry. Stool was tested for norovirus by real-time reverse transcription polymerase chain reaction. Norovirus genotype was then determined by sequencing.

Results: Norovirus was detected in 302 of 1465 (21%) AGE cases and 52 of 826 (6%) healthy controls. Norovirus AGE cases were 2.8-fold more likely than norovirus-negative controls to be secretors (P < .001) in a logistic regression model adjusted for ancestry, age, site, and health insurance. Secretors comprised all 155 cases and 21 asymptomatic infections with the most prevalent norovirus, GII.4. Control children of Meso-American ancestry were more likely than children of European or African ancestry to be secretors (96% vs 74%; P < .001).

Conclusions: FUT2 status is associated with norovirus infection and varies by ancestry. GII.4 norovirus exclusively infected secretors. These findings are important to norovirus vaccine trials and design of agents that may block norovirus-HBGA binding.

Keywords: FUT2; diarrhea; gastroenteritis; histo-blood group antigens; norovirus.

Figure 1.

Flow diagram of subject participation in the study, including eligibility assessment, enrollment, specimen collection, testing for norovirus, and final determination of norovirus status. A, Process of acute gastroenteritis (AGE) case inclusion. B, Process of control inclusion. In each panel, the left-hand column of boxes indicates subjects included at each study step; the right-hand column of boxes details the subjects excluded from each study step and the primary reasons for exclusion.

Figure 2.

Stacked bar chart representing the percentage of FUT2 secretors and nonsecretors in norovirus acute gastroenteritis (AGE) cases compared with norovirus-free healthy controls. The first 8 individual bars from the left represent the secretor status distribution of all 302 norovirus AGE cases infected with a specific norovirus genogroup, genotype, or strain. The most commonly detected norovirus genotype, GII.4, was detected in 155 AGE cases. The GII.4 strains identified—New Orleans, Sydney, and Den Haag—were only detected in FUT2 secretors (P < .001, compared with the frequency of secretors in controls). The second most common norovirus genotype, GII.6, also exhibited a secretor specificity (P = .01). Noroviruses GII.1, GII.7, GI, and others, occurred less frequently and did not display secretor specificity. The “Other GII” category represents 4 less commonly detected norovirus GII genotypes (GII.2, GII.3, GII.8, and GII.13) and 1 case coinfected with GII.1 and GI.6. FUT2 secretors represented 76% of the norovirus-free healthy controls (bar, far right), consistent with the expected population frequency. Not depicted are the 52 asymptomatic norovirus carriers who were enrolled as healthy controls. The distribution of strains, and secretor specificity of strains carried asymptomatically, was consistent with the pattern found in norovirus AGE (see text).