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

Abstract

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. Human noroviruses are the dominant cause of outbreaks of acute gastroenteritis. These viruses are also responsible for significant numbers of sporadic infections, are often found in asymptomatic cases, can cause chronic infections, and infect all age groups. Noroviruses are transmitted via the fecal-oral route, and infections often result from consumption of contaminated foods such as bivalves (clams and oysters). Noroviruses have a single-stranded, positive-sense RNA genome of ϳ7.5 kb. The genome contains three open reading frames (ORFs): ORF1 encodes nonstructural proteins, ORF2 encodes a capsid protein (VP1), and ORF3 encodes a minor capsid protein. Human norovirus is difficult to grow in cell cultures, and the exact locations of the cells and the cell type(s) that norovirus infect remain unknown. Expression of the capsid protein in insect cells can generate selfassembled virus-like particles (VLPs) that are morphologically and antigenically similar to the native virion (1). The norovirus particle is composed of 180 copies of VP1, which forms 90 VP1 homodimers. The X-ray crystal structure of norovirus VLPs identified two main domains, the shell (S) domain and the protruding (P) domain (2). The S domain surrounds the viral RNA, whereas the P domain is further subdivided into P1 and P2 subdomains and contains determinants for cell attachment and antigenicity. HUMAN NOROVIRUS AND HISTO-BLOOD GROUP ANTIGENSHuman noroviruses are known to interact with histo-blood group antigens (HBGAs), and this interaction could be important for infection (3-7). HBGAs can be found as soluble antigens in saliva and are expressed on the mucosal epithelium of the digestive tract. Therefore, noroviruses could interact several times with HBGAs during the course of an infection. Interestingly, human noroviruses can naturally bioaccumulate in bivalves, where they are thought to bind HBGA-like carbohydrates in the gastrointestinal epithelial cells (8). However, this accumulation does not appear to cause harm to the bivalves.Multiple gene families control human HBGA biosynthesis through the action of glycosyltransferases (9). As HBGAs can be either lipid or protein ...

The Human Milk Glycome as a Defense Against Infectious Diseases: Rationale, Challenges, and Opportunities

“…These structural similarities would allow HMOs to act as natural decoys for the HBGA binding pocket of noroviruses. 53,54 Similar findings by the Newburg lab have been seen for C. jejuni wherein α -1,2 fucosylated HMOs were able to inhibit adherence to host cell receptors. 55,56 A summary of HMO-fostered protections against numerous bacterial pathogens is provided in Table 3.…”

Central carbon metabolism is an intrinsic factor for optimal replication of a norovirus

“…These metabolites are part of the glucuronic acid pathway that can lead to the generation of proteoglycans and other glycosylated forms of proteins (54) that have variable roles, including as potential extracellular signals (55, 56). Indeed, many hNoV strains, including the clinically relevant genogroup II, genotype 4 viruses, are able to bind to host extracellular glycans, i.e., histo-blood group antigens (57, 58). Collectively, our metabolomics survey suggests that macrophages respond to MNV infection by increasing: (i) the energy- and metabolite-generating pathways glycolysis and oxidative phosphorylation; (ii) adenosine catabolism, which may be a part of the general innate immune response; and, (iii) the glucuronic acid pathway, which may have effects on cellular protein glycosylation.…”

Human Milk Oligosaccharides as Promising Antivirals

“…The progress was routinely utilized to characterize carbohydrate complexes of different virus families, of which a few accounted for HMO‐viral capsid complexes. Solved to near atomic resolutions, these structures described vital carbohydrate epitope elements that need to be considered when selecting HMO antivirals and provide basis for the future HMO drug design …”

“…Solved to near atomic resolutions, these structures described vital carbohydrate epitope elements that need to be considered when selecting HMO antivirals and provide basis for the future HMO drug design. [14,95,120] Thermodynamic insights into the protein-glycan binding events can be gained by isothermal titration calorimetry or surface plasmon resonance. The former is often the first option for inhibition assays, as it provides fast and accurate results on the binding kinetics, yet requires smaller aliquots of label-free samples.…”