Structural Basis for Norovirus Inhibition by Human Milk Oligosaccharides

Histo-blood group antigens (HBGAs) are important binding factors for norovirus infections. We show that two human milk oligosaccharides, 2′-fucosyllactose (2′FL) and 3-fucosyllactose (3FL), could block norovirus from binding to surrogate HBGA samples. We found that 2′FL and 3FL bound at the equivalent HBGA pockets on the norovirus capsid using X-ray crystallography. Our data revealed that 2′FL and 3FL structurally mimic HBGAs. These results suggest that 2′FL and 3FL might act as naturally occurring decoys in humans.

Download Full-text

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

Journal of Virology ◽

10.1128/jvi.00317-16 ◽

2016 ◽

Vol 90 (13) ◽

pp. 5855-5859 ◽

Cited By ~ 34

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.

Download Full-text

Avidity of α-fucose on human milk oligosaccharides and blood group–unrelated oligo/polyfucoses is essential for potent norovirus-binding targets

Journal of Biological Chemistry ◽

10.1074/jbc.ra117.001369 ◽

2018 ◽

Vol 293 (30) ◽

pp. 11955-11965 ◽

Cited By ~ 14

Author(s):

Franz-Georg Hanisch ◽

Grant S. Hansman ◽

Vasily Morozov ◽

Clemens Kunz ◽

Horst Schroten

Keyword(s):

Human Milk ◽

Blood Group ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides

Download Full-text

Histo-Blood Group Antigen and Human Milk Oligosaccharides

Advances in Experimental Medicine and Biology - Protecting Infants through Human Milk ◽

10.1007/978-1-4757-4242-8_13 ◽

2004 ◽

pp. 135-143 ◽

Cited By ~ 62

Author(s):

Jacques Le Pendu

Keyword(s):

Human Milk ◽

Blood Group ◽

Blood Group Antigen ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides

Download Full-text

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

mSphere ◽

10.1128/msphere.00049-16 ◽

2016 ◽

Vol 1 (2) ◽

Cited By ~ 22

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.

Download Full-text

Structural basis for the interaction between human milk oligosaccharides and the bacterial lectin PA-IIL of Pseudomonas aeruginosa

Biochemical Journal ◽

10.1042/bj20050079 ◽

2005 ◽

Vol 389 (2) ◽

pp. 325-332 ◽

Cited By ~ 94

Author(s):

Stéphanie Perret ◽

Charles Sabin ◽

Claire Dumon ◽

Martina Pokorná ◽

Catherine Gautier ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Human Milk ◽

Bacterial Infections ◽

Pathogenic Bacteria ◽

Dissociation Constants ◽

Structural Information ◽

Structural Basis ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Lewis A

One of the mechanisms contributing to the protection by breast-feeding of the newborn against enteric diseases is related to the ability of human milk oligosaccharides to prevent the attachment of pathogenic bacteria to the duodenual epithelium. Indeed, a variety of fucosylated oligosaccharides, specific to human milk, form part of the innate immune system. In the present study, we demonstrate the specific blocking of PA-IIL, a fucose-binding lectin of the human pathogen Pseudomonas aeruginosa, by milk oligosaccharides. Two fucosylated epitopes, Lewis a and 3-fucosyl-lactose (Lewis x glucose analogue) bind to the lectin with dissociation constants of 2.2×10−7 M and 3.6×10−7 M respectively. Thermodynamic studies indicate that these interactions are dominated by enthalpy. The entropy contribution is slightly favourable when binding to fucose and to the highest-affinity ligand, Lewis a. The high-resolution X-ray structures of two complexes of PA-IIL with milk oligosaccharides allow the precise determination of the conformation of a trisaccharide and a pentasaccharide. The different types of interaction between the oligosaccharides and the protein involve not only hydrogen bonding, but also calcium- and water-bridged contacts, allowing a rationalization of the thermodynamic data. This study provides important structural information about compounds that could be of general application in new therapeutic strategies against bacterial infections.

Download Full-text