By age five, 1 in 6 U.S. children have had a case of medically attended norovirus acute gastroenteritis (AGE). Norovirus is the leading cause of U.S. pediatric AGE, with reported cases rising 52% in 2012 due to the emergence of a novel strain. The purpose of this study is to determine the contribution of the FUT2 (secretor) gene to the population burden of pediatric AGE, particularly norovirus-associated AGE. The FUT2 gene enzyme controls the production of certain sugars at the gut surface, and is hypothesized to be involved in AGE pathogen susceptibility by modifying the surface where AGE pathogens first interact with the host. Noroviruses in particular bind to the sugars synthesized by FUT2 gene enzymes. Nearly 25% of the U.S. population lacks a functional FUT2 gene;these individuals are known as "non- secretors." Several challenge studies and outbreak investigations have shown that non-secretors are resistant to infection by certain strains of noroviruses. However, this association does not hold for all strains, and no studies to date have explored the impact of this genetic variant on population-wide patterns of norovirus AGE. Additionally, few studies have explored the extent to which non-secretors may still shed the virus- thus potentially infecting others- even if they are protected from symptomatic infection by certain strains. The proposed research tests the central hypothesis that secretor genetics determines the population risk of norovirus symptomatic infection and asymptomatic shedding as well as overall AGE susceptibility. For this study, active AGE surveillance was conducted at six pediatric institutions across the country in affiliation with the New Vaccine Surveillance Network (NVSN) of the Centers for Disease Control and Prevention (CDC). Stool (for pathogen testing) and saliva (for DNA genotyping) were collected from 1505 AGE cases and 827 healthy control children under the age of five from December 2011- November 2012. Projections based on preliminary analyses show that at least 300 of these cases will be norovirus positive, including a significant number of cases infected by the 2012 emerging norovirus strain. The proposed research has two specific aims: (1) Determine the association between FUT2 (secretor) genotype and risk of pediatric AGE detected through a national surveillance network and (2) Compare asymptomatic shedding of norovirus in secretors vs. non-secretors. This work has direct
to the design of ongoing norovirus vaccine trials, potential future AGE therapeutics, and personnel assignment during outbreaks. The proposed research gives the fellowship applicant training opportunities in molecular techniques, epidemiology field work, and clinical practice as part of a national multidisciplinary infectious disease surveillance team. The research, training plan, and mentoring team are uniquely tailored to meet the applicant's long-term career goal to become an infectious diseases physician-epidemiologist. PUBLIC HEALTH RELEVANCE: Germs which cause gastroenteritis, such as norovirus, often infect humans by binding to certain carbohydrates at the surface of the human gut. One quarter of the U.S. population has a mutation in the gene FUT2 which keeps them from expressing these carbohydrates in the gut, thus potentially making it more difficult to get gastroenteritis. This study will look at the FUT2 gene in over 2000 U.S. children with and without gastroenteritis to see how this gene impacts the burden of gastroenteritis in U.S. children.