GII.13/21 Noroviruses Recognize Glycans with a Terminal β-Galactose via an Unconventional Glycan Binding Site

Abstract

Human noroviruses (huNoVs) recognize histo-blood group antigens (HBGAs) as host susceptibility factors. GII.13 and GII.21 huNoVs form a unique genetic lineage that emerged from mainstream GII NoVs via development of a new, nonconventional glycan binding site (GBS) that binds Lea antigen. This previous finding raised the question of whether the new GII.13/21 GBS really has such a narrow glycan binding spectrum. In this study, we provide solid phenotypic and structural evidence indicating that this new GBS recognizes a group of glycans with a common terminal β-galactose (β-Gal). First, we found that P domain proteins of GII.13/21 huNoVs circulating at different times bound three glycans sharing a common terminal β-Gal, including Lec, lactose, and mucin core 2. Second, we solved the crystal structures of the GII.13 P dimers in complex with Lec and mucin core 2, which showed that β-Gal is the major binding saccharide. Third, nonfat milk and lactose blocked the GII.13/21 P domain-glycan binding, which may explain the low prevalence of GII.13/21 viruses. Our data provide new insight into the host interactions and epidemiology of huNoVs, which would help in the control and prevention of NoV-associated diseases. IMPORTANCE Evidence from both phenotypic binding assay and structural study support the observed interactions of human noroviruses (huNoVs) with histo-blood group antigens (HBGAs) as receptors or attachment factors, affecting their host susceptibility. GII.13 and GII.21 genotypes form a unique genetic lineage that differs from the mainstream GII huNoVs in their unconventional glycan binding site. Unlike the previous findings that GII.13/21 genotypes recognize only Lea antigen, we found in this study that they can interact with a group of glycans with a common terminal β-Gal, including Lec, lactose, and mucin core 2. However, this wide glycan binding spectrum in a unique binding mode of the GII.13/21 huNoVs appears not to increase their prevalence, probably due to the existence of decoy glycan receptors in human gastrointestinal tract limiting their infection. Our findings shed light on the host interaction and epidemiology of huNoVs, which would impact the strategy of huNoV control and prevention.

Global prevalence and genotype distribution of norovirus infection in children with gastroenteritis: A meta‐analysis on 6 years of research from 2015 to 2020

“…ORF2 and ORF3 also encode the major and minor structural viral capsid proteins VP1 and VP2, respectively. 17 NoVs are classified into 10 distinct genogroups (GI-GX), of which GI, GII and GIV genogroups are associated with the majority of infections in humans. 18 The genogroups are further divided into genotypes which are defined based on the divergence of the VP1 amino acid sequence.…”

Full-genome sequences of GII.13[P21] recombinant norovirus strains from an outbreak in Changsha, China

“…The ORF2 fragment of these strains belonged to the GII.13 genotype branch and shared 98.2% sequence identity with MG892908 (Fig. 2B) [15]. This site consists of eight residues located at the top of each P domain.…”

“…17[P17]. However, these genotypes are found infrequently in human infections, and this might be associated with a unique histo-blood group antigen (HBGA) binding site involved in host susceptibility and the presence of decoy glycan receptors in the human gastrointestinal tract that prevents binding of the virus [15,16].…”

Structural basis of host ligand specificity change of GII porcine noroviruses from their closely related GII human noroviruses

“…The two residue mutations in GII.11 and GII.19 porNoVs that have been shown to damage the HBGA function are shown in green letters. For clarity, the unique genetic lineage formed by GII.13 and GII.21 genotypes that use a completely different HBS is not included in this analysis [21,53,54]. The full VP1 sequences for this analysis can be accessed from GenBank via the following codes: AY038600 (GII.4/VA387), EU373815 (GII.20/Lucken), AY130762 (GII.15/J23), AF414409 (GII.7/Gwyned), AF195848 (GII.8/Amster), AAK84676 (GII.9/VA207), AY130761 (GII.14/M7), U02030 (GII.3/TV24), AF414407 (GII.6/Florid), AY823304 (GII.18/QW101), AY823306 (GII.19/QW170), AY077644 (GII.11/VA34), KR020503 (GII.17/Guang), AB083780 (GII.22/YURI), U07611 (GII.1/Hawaii), AB044366 (GII.12/Hiro), AY502010 (GII.16/Tiffin), AF504671 (GII.10/VN026), AF397156 (GII.5/MOH), and AY134748 (GII.2/SMV).…”