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

Abstract

Human 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. IMPORTANCE Our 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.

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

“…The glycan binding profiles of huNoVs have been shown to be associated with their infection risk (3, 24–29), and possibly also their prevalence (19, 21). We showed that the GII.13/21 huNoVs with the new GBS recognize a broad spectrum of terminal β-Gal-containing glycans, including mucin core 2.…”

“…For example, a new variant of the previously rare genotype GII.17 became the predominant strain to cause outbreaks during the epidemic season of 2014–2015 (17, 18). Along with the antigenic change (17), the new GII.17 variant had a broader HBGA binding spectrum due to minor mutations at the conserved GII glycan binding site (GBS) (18–21). Therefore, identification of the new huNoV-glycan interactions, especially those of the rare genotypes, is necessary to help in the prevention and control of huNoV-associated diseases.…”

Fondness for sugars of enteric viruses confronts them with human glycans genetic diversity

“…Structural analyses described the interactions between the virus capsid protein protruding domain (P-domain) and various HBGA oligosaccharides. Several distinct binding sites and modes of binding across the norovirus strains diversity have thus been uncovered, illustrating the adaptation of noroviruses to the human gut glycan diversity (Bu et al 2008;Cao et al 2007;Chen et al 2011;Choi et al 2008;Hansman et al 2011;Koromyslova et al 2015;Kubota et al 2012;Qian et al 2018;Shanker et al 2014;Singh et al 2015a).…”

“…An impact of the ABO phenotypes has also been reported, again with disparities across studies, likely explained by variations in the strains patterns of glycan recognition (Ruvöen-Clouet et al 2013). variants, which could contribute to their strong epidemiological impact (Chan et al 2015;Qian et al 2018;Zhang et al 2015). Unlike GII.4 strains, these emergent GII.17 strains failed to become dominant outside Asian countries where the major FUT2 mutant alleles confer a weak, albeit not null, secretor phenotype that potentially expands the susceptible fraction of the population (Ferrer-Admetlla et al 2009;Pang et al 2001).…”

Capturing noroviruses circulating in the population: sewage surveillance in Guangdong, China (2013-2018)

“…Outbreak surveillance mostly identifies the genotypes that may already be efficiently transmitted in the population, and it is difficult to detect those variants before they are established in the local population. In particular, NoV genotypes such as GII.4 and GII.17 can have sudden transitions in their antigenicity or infectivity through a few amino acid mutations in their structural proteins (28)(29)(30). Before the transitions, the variants may have limited infectivity and circulate in the population at a relatively low level.…”