Abstract
Neonatal rotavirus infections are predominantly asymptomatic. While an association with gastrointestinal symptoms has been described in some settings, factors influencing differences in clinical presentation are not well understood. Using multidisciplinary approaches, we show that a complex interplay between human milk oligosaccharides (HMOs), milk microbiome, and infant gut microbiome impacts neonatal rotavirus infections. Validating in vitro studies where HMOs are not decoy receptors for neonatal strain G10P[11], population studies show significantly higher levels of Lacto-N-tetraose (LNT), 2’-fucosyllactose (2’FL), and 6’-siallylactose (6’SL) in milk from mothers of rotavirus-positive neonates with gastrointestinal symptoms. Further, these HMOs correlate with abundance of Enterobacter/Klebsiella in maternal milk and infant stool. Specific HMOs also improve the infectivity of a neonatal strain-derived rotavirus vaccine. This study provides molecular and translational insight into host factors influencing neonatal rotavirus infections and identifies maternal components that could promote the performance of live, attenuated rotavirus vaccines.
Highlights
Since structures analogous to precursor histo-blood group antigens (HBGAs) are present in human milk and P[11] VP8* binds human milk oligosaccharides (HMOs) on a shotgun milk glycan array21, we hypothesized that HMOs act as decoy receptors, competitively inhibiting the binding of G10P[11] to intestinal HBGAs and that differences in expression of such HMOs may explain the differences in clinical presentation between neonates
To elucidate the biological relevance of these interactions and determine whether HMOs act as soluble decoy receptors for G10P[11], infectivity assays were carried out on African green monkey kidney epithelial cells (MA104 cells), a well-established model for rotavirus studies in vitro, using increasing concentrations of LNT and LNnT
Human breast milk contains over 100 different oligosaccharides, including other structures similar to developmentally regulated precursor HBGAs with potential decoy activity
Summary
Validating in vitro studies where HMOs are not decoy receptors for neonatal strain G10P[11], population studies show significantly higher levels of Lacto-N-tetraose (LNT), 2’-fucosyllactose (2’FL), and 6’siallylactose (6’SL) in milk from mothers of rotavirus-positive neonates with gastrointestinal symptoms These HMOs correlate with abundance of Enterobacter/Klebsiella in maternal milk and infant stool. Human milk oligosaccharides (HMOs) are the third most abundant solid component after lactose and lipids These unconjugated complex glycans act as prebiotics, antiadhesives, and antimicrobials and play critical roles in altering epithelial and immune cell responses. We focused on a unique rotavirus strain called G10P [11] that has been associated with a stable and high incidence of almost exclusive neonatal infections in Vellore, India15 In this setting, G10P[11] is associated with both severe gastrointestinal symptoms as well as asymptomatic infections. HMOs enhance the infectivity of a licensed P [11] rotavirus vaccine, highlighting maternal factors that could promote the performance of live, attenuated vaccines
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