Histo-blood group antigens of glycosphingolipids predict susceptibility of human intestinal enteroids to norovirus infection

• Published in: The Journal of biological chemistry Vol. 295; no. 47; pp. 15974 - 15987
• Main Authors: Rimkute, Inga, Thorsteinsson, Konrad, Henricsson, Marcus, Tenge, Victoria R., Yu, Xiaoming, Lin, Shih-Ching, Haga, Kei, Atmar, Robert L., Lycke, Nils, Nilsson, Jonas, Estes, Mary K., Bally, Marta, Larson, Göran
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.11.2020; American Society for Biochemistry and Molecular Biology
• Subjects: Biochemistry & Molecular Biology; Biochemistry and Molecular Biology; Biokemi och molekylärbiologi; Blood Group Antigens - metabolism; Caliciviridae Infections - metabolism; Caliciviridae Infections - pathology; cell-surface antigens; ceramide; characterization; epithelial-cells; expression; fetal tissue; fucosyltransferase; glycerophospholipid; Glycobiology and Extracellular Matrices; glycolipid structure; glycosphingolipid; Glycosphingolipids - metabolism; glycosylation; host-pathogen interaction; human norovirus; Humans; intestinal epithelium; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestinal Mucosa - virology; intestine; meconium; membrane-properties; mini-guts; molecular; Norovirus - metabolism; Organoids - metabolism; Organoids - pathology; Organoids - virology; plus-stranded RNA virus; replication; sphingolipid; sphingomyelin; stem-cells; viral; viral replication; Virus Attachment; virus entry; virus-like particles; host-pathogen interaction; intestine; sphingolipid; glycosphingolipid; glycosylation; fucosyltransferase; viral replication; ceramide; plus-stranded RNA virus; virus entry; glycerophospholipid; sphingomyelin; intestinal epithelium; glycolipid structure; human norovirus
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.RA120.014855

The molecular mechanisms behind infection and propagation of human restricted pathogens such as human norovirus (HuNoV) have defied interrogation because they were previously unculturable. However, human intestinal enteroids (HIEs) have emerged to offer unique ex vivo models for targeted studies of intestinal biology, including inflammatory and infectious diseases. Carbohydrate-dependent histo-blood group antigens (HBGAs) are known to be critical for clinical infection. To explore whether HBGAs of glycosphingolipids contribute to HuNoV infection, we obtained HIE cultures established from stem cells isolated from jejunal biopsies of six individuals with different ABO, Lewis, and secretor genotypes. We analyzed their glycerolipid and sphingolipid compositions and quantified interaction kinetics and the affinity of HuNoV virus-like particles (VLPs) to lipid vesicles produced from the individual HIE-lipid extracts. All HIEs had a similar lipid and glycerolipid composition. Sphingolipids included HBGA-related type 1 chain glycosphingolipids (GSLs), with HBGA epitopes corresponding to the geno- and phenotypes of the different HIEs. As revealed by single-particle interaction studies of Sydney GII.4 VLPs with glycosphingolipid-containing HIE membranes, both binding kinetics and affinities explain the patterns of susceptibility toward GII.4 infection for individual HIEs. This is the first time norovirus VLPs have been shown to interact specifically with secretor gene–dependent GSLs embedded in lipid membranes of HIEs that propagate GII.4 HuNoV ex vivo, highlighting the potential of HIEs for advanced future studies of intestinal glycobiology and host-pathogen interactions.