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Structural Insight into Terminal Galactose Recognition by Two Non-HBGA Binding GI.3 Noroviruses.

ABSTRACT: Human noroviruses (huNoVs) cause epidemic acute gastroenteritis using histo-blood group antigens (HBGAs) as host receptors or attachment factors to initiate an infection. While most huNoVs have been shown to bind HBGAs, some known clinical isolates, such as GI.3 DSV and VA115, do not recognize any HBGAs and thus the molecular mechanism behind their infections remains elusive. In this study, we provided both phenotypic and structural evidence to show that huNoV DSV and VA115 recognize a group of glycans with terminal galactoses as ligands. First, through glycan array we found that both DSV and VA115 protruding (P) domain proteins bound two oligosaccharides that share common terminal galactoses. Then, by determination of the crystal structures of DSV/VA115 P proteins in complex with Galα1-3Galβ1-4Glc and/or NA2 N-Glycan, respectively, we showed that the terminal galactose is the main saccharide recognized by the two viral proteins. Our data demonstrated that GI huNoVs can interact with non-HBGA glycans through their conserved galactose binding site, shedding light on the mechanism of huNoV adaptation through recognizing new glycan receptors to facilitate their widespread nature in human population. These findings are also of significance in strategy development for huNoV control and prevention, as well as development of antiviral drugs. IMPORTANCE Human noroviruses (huNoVs) are the most important viral pathogens causing epidemic acute gastroenteritis worldwide. Previous studies indicated that histo-blood group antigens (HBGAs) are critical host-susceptibility factors affecting huNoV host susceptibility, host range, and probably prevalence. However, certain huNoVs, such as GI.3 DSV and VA115, do not recognize any HBGAs. This implies that other unknown host factors might exist and the molecular mechanism underlying their host receptor recognition or attachment remains elusive. In this study, we found that purified capsid protruding domain proteins from two GI.3 huNoVs specifically bind two glycans that contain a common terminal galactose. We solved the crystal structures of the complexes at atomic resolution and validated the vital amino acids involved in glycan recognition. Our findings elucidate the mechanism of GI.3 huNoV-non-HBGA glycan interaction, which explains why GI.3 virus strains could not bind human HBGAs, paving a way to the prevention and treatment of huNoV-associated diseases.

SUBMITTER: Wang C

PROVIDER: S-EPMC9278146 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:Noroviruses (NoV) are the main etiological agents of gastroenteritis outbreaks worldwide and susceptibility to NoV infection has been related to the histo-blood group antigen (HBGA). This study aimed to determine the prevalence of NoV strains and to evaluate the HBGA phenotype and genotype of children from semi-isolated Quilombola communities, descendents of black slaves in Brazil. A total of 397 children up to eleven years old, with and without diarrhea, from Quilombola Communities in the Espirito Santo State, Brazil, were investigated for the presence of NoV from August 2007 to September 2009. Feces were collected from all the children, and blood from the NoV positive children. NoV was screened by reverse transcription-PCR with primers for the RNA-dependent RNA polymerase region; genogroup was determined by PCR with primers for the C and D regions and genotyped by sequencing. HBGA phenotype was performed by gel-spinning and FUT2 and FUT3 were analyzed by PCR or sequencing analysis. NoV were detected in 9.2% (12/131) of diarrheic and 1.5% (4/266) of non-diarrheic children (p<0.05, Fisher's exact test). GI and GII genogroups were present in 12.5% and 87.5% of the samples, respectively. The following genotypes were characterized: GII.4 (25%), GII.12 (25%), GII.6 (12.5%) and GI.1 (6.3%), GI.3 (12.5%) and GI.4 (6.3%). Children infected with NoV showed the A (n?=?6), O (n?=?6), and B (n?=?2) HBGA phenotypes, and 13 of them were classified as secretors (Se) and one as a non secretor (se). Mutations of Se (40), (171,216,357,428,739,960) were found for the FUT2 gene and mutations of Le (59, 202, 314) for the FUT3 gene. The only se child was infected by NoV GI, whereas the Se children were indiscriminately infected by GI or GII. This study showed rates of NoV infection in symptomatic and asymptomatic Quilombola children consistent with other studies. However, children under 12 months were seven times more affected than those between 1 and 5 years old. GII.12 was as frequent as GII.4 and GI.1 and GI.4 were described for the first time in Brazil. Owing to the small number of cases studied, no clear pattern of susceptibility and/or HBGA resistance could be inferred.

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Structural Insight into Terminal Galactose Recognition by Two Non-HBGA Binding GI.3 Noroviruses.

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