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

2019 ◽  
Vol 93 (15) ◽  
Author(s):  
Xin Cong ◽  
Xiao-man Sun ◽  
Jian-xun Qi ◽  
Han-bo Li ◽  
Wen-gang Chai ◽  
...  
Keyword(s):  
Binding Site ◽  
Blood Group ◽  
Binding Mode ◽  
Host Susceptibility ◽  
Genetic Lineage ◽  
Blood Group Antigens ◽  
Human Noroviruses ◽  
Control And Prevention ◽  
P Domain ◽  
Glycan Receptors

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.

scholarly journals Human Group C Rotavirus VP8*s Recognize Type A Histo-Blood Group Antigens as Ligands

2018 ◽  
Vol 92 (11) ◽  
Author(s):  
Xiaoman Sun ◽  
Lihong Wang ◽  
Jianxun Qi ◽  
Dandi Li ◽  
Mengxuan Wang ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Blood Group ◽  
Specific Interaction ◽  
Type A ◽  
Host Susceptibility ◽  
Structural Basis ◽  
Receptor Interaction ◽  
Blood Group Antigens ◽  
Group Species

ABSTRACTGroup/species C rotaviruses (RVCs) have been identified as important pathogens of acute gastroenteritis (AGE) in children, family-based outbreaks, as well as animal infections. However, little is known regarding their host-specific interaction, infection, and pathogenesis. In this study, we performed serial studies to characterize the function and structural features of a human G4P[2] RVC VP8* that is responsible for the host receptor interaction. Glycan microarrays demonstrated that the human RVC VP8* recognizes type A histo-blood group antigens (HBGAs), which was confirmed by synthetic glycan-/saliva-based binding assays and hemagglutination of red blood cells, establishing a paradigm of RVC VP8*-glycan interactions. Furthermore, the high-resolution crystal structure of the human RVC VP8* was solved, showing a typical galectin-like structure consisting of two β-sheets but with significant differences from cogent proteins of group A rotaviruses (RVAs). The VP8* in complex with a type A trisaccharide displays a novel ligand binding site that consists of a particular set of amino acid residues of the C-D, G-H, and K-L loops. RVC VP8* interacts with type A HBGAs through a unique mechanism compared with that used by RVAs. Our findings shed light on the host-virus interaction and the coevolution of RVCs and will facilitate the development of specific antivirals and vaccines.IMPORTANCEGroup/species C rotaviruses (RVCs), members ofReoviridaefamily, infect both humans and animals, but our knowledge about the host factors that control host susceptibility and specificity is rudimentary. In this work, we characterized the glycan binding specificity and structural basis of a human RVC that recognizes type A HBGAs. We found that human RVC VP8*, the rotavirus host ligand binding domain that shares only ∼15% homology with the VP8* domains of RVAs, recognizes type A HBGA at an as-yet-unknown glycan binding site through a mechanism distinct from that used by RVAs. Our new advancements provide insights into RVC-cell attachment, the critical step of virus infection, which will in turn help the development of control and prevention strategies against RVs.

scholarly journals Human Noroviruses' Fondness for Histo-Blood Group Antigens

2014 ◽  
Vol 89 (4) ◽  
pp. 2024-2040 ◽  
Author(s):  
Bishal K. Singh ◽  
Mila M. Leuthold ◽  
Grant S. Hansman
Keyword(s):  
Crystal Structures ◽  
Blood Group ◽  
Enteric Bacteria ◽  
Blood Group Antigens ◽  
Binding Interactions ◽  
Human Noroviruses ◽  
X Ray ◽  
P Domain ◽  
Lewis Y ◽  
Binding Mechanisms

ABSTRACTHuman noroviruses are the dominant cause of outbreaks of gastroenteritis around the world. Human noroviruses interact with the polymorphic human histo-blood group antigens (HBGAs), and this interaction is thought to be important for infection. Indeed, synthetic HBGAs or HBGA-expressing enteric bacteria were shown to enhance norovirus infection in B cells. A number of studies have found a possible relationship between HBGA type and norovirus susceptibility. The genogroup II, genotype 4 (GII.4) noroviruses are the dominant cluster, evolve every other year, and are thought to modify their binding interactions with different HBGA types. Here we show high-resolution X-ray crystal structures of the capsid protruding (P) domains from epidemic GII.4 variants from 2004, 2006, and 2012, cocrystallized with a panel of HBGA types (H type 2, Lewis Y, Lewis B, Lewis A, Lewis X, A type, and B type). Many of the HBGA binding interactions were found to be complex, involving capsid loop movements, alternative HBGA conformations, and HBGA rotations. We showed that a loop (residues 391 to 395) was elegantly repositioned to allow for Lewis Y binding. This loop was also slightly shifted to provide direct hydrogen- and water-mediated bonds with Lewis B. We considered that the flexible loop modulated Lewis HBGA binding. The GII.4 noroviruses have dominated outbreaks over the past decade, which may be explained by their exquisite HBGA binding mechanisms, their fondness for Lewis HBGAs, and their temporal amino acid modifications.IMPORTANCEOur data provide a comprehensive picture of GII.4 P domain and HBGA binding interactions. The exceptionally high resolutions of our X-ray crystal structures allowed us to accurately recognize novel GII.4 P domain interactions with numerous HBGA types. We showed that the GII.4 P domain-HBGA interactions involved complex binding mechanisms that were not previously observed in norovirus structural studies. Many of the GII.4 P domain-HBGA interactions we identified were negative in earlier enzyme-linked immunosorbent assay (ELISA)-based studies. Altogether, our data show that the GII.4 norovirus P domains can accommodate numerous HBGA types.

scholarly journals Structural Adaptations of Norovirus GII.17/13/21 Lineage through Two Distinct Evolutionary Paths

2018 ◽  
Vol 93 (1) ◽  
Author(s):  
Ying Qian ◽  
Mohan Song ◽  
Xi Jiang ◽  
Ming Xia ◽  
Jarek Meller ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Host Susceptibility ◽  
Genetic Lineage ◽  
Human Norovirus ◽  
Human Noroviruses ◽  
Evolutionary Changes ◽  
Evolutionary Paths ◽  
Molecular Bases ◽  
Structural Adaptations

ABSTRACTHuman noroviruses (huNoVs), which cause epidemic acute gastroenteritis, recognize histo-blood group antigens (HBGAs) as host attachment factors affecting host susceptibility. HuNoVs are genetically diverse, containing at least 31 genotypes in the two major genogroups (genogroup I [GI] and GII). Three GII genotypes, GII genotype 17 (GII.17), GII.13, and GII.21, form a unique genetic lineage, in which the GII.17 genotype retains the conventional GII HBGA binding site (HBS), while the GII.13/21 genotypes acquire a completely new HBS. To understand the molecular bases behind these evolutionary changes, we solved the crystal structures of the HBGA binding protruding domains of (i) an early GII.17 variant (the 1978 variant) that does not bind or binds weakly to HBGAs, (ii) the new GII.17 variant (the 2014/15 variant) that binds A/B/H antigens strongly via an optimized GII HBS, and (iii) a GII.13 variant (the 2010 variant) that binds the Lewis a (Lea) antigen via the new HBS. These serial, high-resolution structural data enable a comprehensive structural comparison to understand the evolutionary changes of the GII.17/13/21 lineage, including the emergence of the new HBS of the GII.13/21 sublineage and the possible HBS optimization of the recent GII.17 variant for an enhanced HBGA binding ability. Our study elucidates the structural adaptations of the GII.17/13/21 lineage through distinct evolutionary paths, which may allow a theory explaining huNoV adaptations and evolutions to be put forward.IMPORTANCEOur understanding of the molecular bases behind the interplays between human noroviruses and their host glycan ligands, as well as their evolutionary changes over time with alterations in their host ligand binding capability and host susceptibility, remains limited. By solving the crystal structures of the glycan ligand binding protruding (P) domains with or without glycan ligands of three representative noroviruses of the GII.17/13/21 genetic lineage, we elucidated the molecular bases of the human norovirus-glycan interactions of this special genetic lineage. We present solid evidence on how noroviruses of this genetic lineage evolved via different evolutionary paths to (i) optimize their glycan binding site for higher glycan binding function and (ii) acquire a completely new glycan binding site for new ligands. Our data shed light on the mechanism of the structural adaptations of human noroviruses through different evolutionary paths, facilitating our understanding of human norovirus adaptations, evolutions, and epidemiology.

scholarly journals Non-secretion of ABO blood group antigens as a host susceptibility factor in the spondyloarthropathies.

BMJ ◽  
1987 ◽  
Vol 294 (6566) ◽  
pp. 208-210 ◽  
Author(s):  
R Shinebaum ◽  
C C Blackwell ◽  
P J Forster ◽  
N P Hurst ◽  
D M Weir ◽  
...  
Keyword(s):  
Blood Group ◽  
Host Susceptibility ◽  
Abo Blood Group ◽  
Blood Group Antigens ◽  
Susceptibility Factor

scholarly journals Histochemical reactivity of the Geodia cydonium agglutinin (GCA) in human tissues.

1991 ◽  
Vol 39 (4) ◽  
pp. 491-505 ◽  
Author(s):  
M Vierbuchen ◽  
G Uhlenbruck ◽  
F G Hanisch ◽  
W E Müller ◽  
M Ortmann ◽  
...  
Keyword(s):  
Binding Site ◽  
Blood Group ◽  
Lectin Binding ◽  
Blood Group Antigens ◽  
Group Status ◽  
Geodia Cydonium ◽  
Group A ◽  
Complex Carbohydrates ◽  
Group B ◽  
Inhibition Studies

We applied a peroxidase-antiperoxidase technique to study the distribution pattern and binding characteristics of the lectin from the marine sponge Geodia cydonium (Geodia cydonium agglutinin; GCA) in various human tissues. This lectin has been shown to possess a broad reactivity, but there was a distinct distribution of binding sites within the different organs. In the histochemical system GCA displayed no blood group specificity and labeled red blood cells, the vascular endothelium, and epithelial cells showing blood group antigen expression independent of the ABH blood group status. However, inhibition of GCA reactivity by simple sugars and complex carbohydrates demonstrated tissue-specific differences of lectin binding related to the ABH blood group status of the tissue and revealed information on the structural requirements of the histological lectin binding site. Tissues that totally lacked blood group antigens or that expressed only the H-antigen disclosed a GCA reactivity which was completely inhibited by lactose. In contrast, tissues that expressed blood group A- or blood group B-antigen exhibited a lactose-resistant lectin binding which was inhibited only by water-soluble blood group substance A from peptone A and by bovine glycophorin but not by other complex carbohydrates, including human glycophorin and human asialoglycophorin. Competitive inhibition studies in situ revealed that GCA binding was not inhibited by blood group type I/II carbohydrate sequence-specific lectins or by lectins with other sugar specificities. Inhibition by lactose of GCA binding to some histological sites indicates that the binding site consists of a beta-linked galactose-containing disaccharide. However, periodate oxidation of tissue sections had no effect on lectin binding, pointing to a subterminal location of the relevant sequence. The results obtained from inhibition studies with simple saccharides and complex carbohydrates in relation to the expression of ABH blood group antigens suggest a complex lectin combining site(s) in histological specimens. The lectin may possess either one binding site with a range of affinities for different carbohydrates (besides beta-linked disaccharides the GCA binding site accommodates to carbohydrate determinants carrying the blood group A or blood group B determinant), or may possess two different binding sites. Besides an acceptor site for beta-linked disaccharides, an additional binding site may exist accommodating to extended carbohydrate sequences related to A or B blood group structures. In conclusion, GCA represents a blood group-nonspecific lectin whose binding affinities are determined by the ABH blood group status of the tissue.

scholarly journals Structural Constraints on Human Norovirus Binding to Histo-Blood Group Antigens

mSphere ◽  
2016 ◽  
Vol 1 (2) ◽  
Author(s):  
Bishal K. Singh ◽  
Mila M. Leuthold ◽  
Grant S. Hansman
Keyword(s):  
Aspartic Acid ◽  
Blood Group ◽  
Blood Group Antigens ◽  
Structural Constraints ◽  
Human Norovirus ◽  
Genotype 4 ◽  
Human Noroviruses ◽  
X Ray ◽  
X Ray Crystallography ◽  
New Findings

ABSTRACT Human norovirus interacts with the polymorphic human histo-blood group antigens (HBGAs), and this interaction is thought to be important for infection. The genogroup II genotype 4 (GII.4) noroviruses are the dominant cluster, evolve every other year, and are thought to modify their binding interactions with different HBGA types. Most human noroviruses bind HBGAs, while some strains were found to have minimal or no HBGA interactions. Here, we explain some possible structural constraints for several noroviruses that were found to bind poorly to HBGAs by using X-ray crystallography. We showed that one aspartic acid was flexible or positioned away from the fucose moiety of the HBGAs and this likely hindered binding, although other fucose-interacting residues were perfectly oriented. Interestingly, a neighboring loop also appeared to influence the loop hosting the aspartic acid. These new findings might explain why some human noroviruses bound HBGAs poorly, although further studies are required.

scholarly journals Structural Basis for the Receptor Binding Specificity of Norwalk Virus

2008 ◽  
Vol 82 (11) ◽  
pp. 5340-5347 ◽  
Author(s):  
Weiming Bu ◽  
Aygun Mamedova ◽  
Ming Tan ◽  
Ming Xia ◽  
Xi Jiang ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Binding Pocket ◽  
Binding Mode ◽  
Structural Basis ◽  
Blood Group Antigens ◽  
Norwalk Virus ◽  
P Domain ◽  
Induced Changes ◽  
Receptor Binding Specificity ◽  
Cocrystal Structure

ABSTRACT Noroviruses are positive-sense, single-stranded RNA viruses that cause acute gastroenteritis. They recognize human histo-blood group antigens as receptors in a strain-specific manner. The structures presented here were analyzed in order to elucidate the structural basis for differences in ligand recognition of noroviruses from different genogroups, the prototypic Norwalk virus (NV; GI-1) and VA387 (GII-4), which recognize the same A antigen but differ in that NV is unable to bind to the B antigen. Two forms of the receptor-binding domain of the norovirus coat protein, the P domain and the P polypeptide, that were previously shown to differ in receptor binding and P-particle formation properties were studied. Comparison of the structures of the NV P domain with and without A trisaccharide and the NV P polypeptide revealed no major ligand-induced changes. The 2.3-Å cocrystal structure reveals that the A trisaccharide binds to the NV P domain through interactions with the residues Ser377, Asp327, His329, and Ser380 in a mode distinct from that previously reported for the VA387 P-domain-A-trisaccharide complex. Mutational analyses confirm the importance of these residues in NV P-particle binding to native A antigen. The α-GalNAc residue unique to the A trisaccharide is buried deeply in the NV binding pocket, unlike in the structures of A and B trisaccharides bound to VA387 P domain, where the α-fucose residue forms the most protein contacts. The A-trisaccharide binding mode seen in the NV P domain complex cannot be sterically accommodated in the VA387 P domain.

Isolation of cross-reactive human monoclonal antibodies that prevent binding of human noroviruses to histo-blood group antigens

2013 ◽  
Vol 86 (4) ◽  
pp. 558-567 ◽  
Author(s):  
Kyoko Higo-Moriguchi ◽  
Haruko Shirato ◽  
Yuichi Someya ◽  
Yoshikazu Kurosawa ◽  
Naokazu Takeda ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Blood Group ◽  
Blood Group Antigens ◽  
Human Monoclonal Antibodies ◽  
Human Noroviruses

scholarly journals Bacterial histo-blood group antigens contributing to genotype-dependent removal of human noroviruses with a microfiltration membrane

2016 ◽  
Vol 95 ◽  
pp. 383-391 ◽  
Author(s):  
Mohan Amarasiri ◽  
Satoshi Hashiba ◽  
Takayuki Miura ◽  
Toyoko Nakagomi ◽  
Osamu Nakagomi ◽  
...  
Keyword(s):  
Blood Group ◽  
Blood Group Antigens ◽  
Human Noroviruses ◽  
Microfiltration Membrane

scholarly journals Human Norovirus Interactions with Histo-Blood Group Antigens and Human Milk Oligosaccharides

2016 ◽  
Vol 90 (13) ◽  
pp. 5855-5859 ◽  
Author(s):  
Horst Schroten ◽  
Franz-Georg Hanisch ◽  
Grant S. Hansman
Keyword(s):  
Virus Infection ◽  
Human Milk ◽  
Blood Group ◽  
Blood Group Antigens ◽  
Human Milk Oligosaccharides ◽  
Binding Studies ◽  
Human Norovirus ◽  
Milk Oligosaccharides ◽  
Human Noroviruses ◽  
Binding Pockets

Human noroviruses interact with both human histo-blood group antigens (HBGAs) and human milk oligosaccharides (HMOs). The former are believed to be important for a virus infection, while the latter might act as natural decoys in the host during an infection. However, certain noroviruses are known to bind poorly to HBGAs and yet still cause infections; some interact with numerous HBGA types but are nonprevalent; and yet others bind HBGAs and seem to be increasing in prevalence. HBGAs and HMOs can be found as soluble antigens in humans, can be structurally alike, and can interact with equivalent residues at identical binding pockets on the capsid. In this Gem, we discuss HBGA and HMO binding studies for human noroviruses, concentrating on the clinically important genogroup II noroviruses. In short, the roles of HBGA and HMO interactions in norovirus infections are still unclear.

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