Virus-Host Interactions Between Nonsecretors and Human Norovirus

• Type of Material: Article
• Authors: Lisa C. Lindesmith, University of North Carolina; Paul D. Brewer-Jensen, University of North Carolina; Michael L. Mallory, University of North Carolina; Kara Jensen, University of North Carolina; Boyd L. Yount, University of North Carolina; Veronica Costantini, Centers for Disease Control and Prevention; Matthew Collins, Emory University; Caitlin E. Edwards, University of North Carolina; Timothy P. Sheahan, University of North Carolina; Jan Vinje, Centers for Disease Control and Prevention; Ralph S. Baric, University of North Carolina
• Language: English
• Date: 2020-01-01
• Publisher: Elsevier Inc.
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jcmgh.2020.03.006
• Title of Journal or Parent Work: Cellular and Molecular Gastroenterology and Hepatology
• Volume: 10
• Issue: 2
• Start Page: 245
• End Page: 267
• Grant/Funding Information: The University of North Carolina Flow Cytometry Core Facility is supported in part by Cancer Center Core support grant P30 CA016086 to the University of North Carolina Lineberger Comprehensive Cancer Center.; This work was supported by grant U19 AI109761 Centers of Excellence for Translational Research from the National Institutes of Health (R.S.B.), grant 203268/Z/16/Z from the Wellcome Trust (R.S.B.), and by the intramural food safety program at the Centers for Disease Control and Prevention (J.V.).
• Keywords: Science & Technology; Replication; Responses; Life Sciences & Biomedicine; Correlate; Susceptibility; Gastroenterology & Hepatology; Infection; Blocking antibodies; Cellular Immunity; Receptor Binding; Blockade Antibody; Bile; Neutralizing Antibody; Cytokines; Protection; GII.4; Gastroenteritis
• Research Categories: Health Sciences, Epidemiology; Biology, Cell; Health Sciences, Public Health

Abstract

Background & Aims Human norovirus infection is the leading cause of acute gastroenteritis. Genetic polymorphisms, mediated by the FUT2 gene (secretor enzyme), define strain susceptibility. Secretors express a diverse set of fucosylated histoblood group antigen carbohydrates (HBGA) on mucosal cells; nonsecretors (FUT2-/-) express a limited array of HBGAs. Thus, nonsecretors have less diverse norovirus strain infections, including resistance to the epidemiologically dominant GII.4 strains. Because future human norovirus vaccines will comprise GII.4 antigen and because secretor phenotype impacts GII.4 infection and immunity, nonsecretors may mimic young children immunologically in response to GII.4 vaccination, providing a needed model to study cross-protection in the context of limited pre-exposure. Methods By using specimens collected from the first characterized nonsecretor cohort naturally infected with GII.2 human norovirus, we evaluated the breadth of serologic immunity by surrogate neutralization assays, and cellular activation and cytokine production by flow cytometry. Results GII.2 infection resulted in broad antibody and cellular immunity activation that persisted for at least 30 days for T cells, monocytes, and dendritic cells, and for 180 days for blocking antibody. Multiple cellular lineages expressing interferon-γ and tumor necrosis factor-α dominated the response. Both T-cell and B-cell responses were cross-reactive with other GII strains, but not GI strains. To promote entry mechanisms, inclusion of bile acids was essential for GII.2 binding to nonsecretor HBGAs. Conclusions These data support development of within-genogroup, cross-reactive antibody and T-cell immunity, key outcomes that may provide the foundation for eliciting broad immune responses after GII.4 vaccination in individuals with limited GII.4 immunity, including young children.