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Population Genomics of GII.4 Noroviruses Reveal Complex Diversification and New Antigenic Sites Involved in the Emergence of Pandemic Strains.

ABSTRACT: GII.4 noroviruses are a major cause of acute gastroenteritis. Their dominance has been partially explained by the continuous emergence of antigenically distinct variants. To gain insights into the mechanisms of viral emergence and population dynamics of GII.4 noroviruses, we performed large-scale genomics, structural, and mutational analyses of the viral capsid protein (VP1). GII.4 noroviruses exhibited a periodic replacement of predominant variants with accumulation of amino acid substitutions. Genomic analyses revealed (i) a large proportion (87%) of conserved residues; (ii) variable residues that map on the previously determined antigenic sites; and (iii) variable residues that map outside the antigenic sites. Residues in the third pattern category formed motifs on the surface of VP1, which suggested extensions of previously predicted and new uncharacterized antigenic sites. The role of two motifs (C and G) in the antigenic makeup of the GII.4 capsid protein was confirmed with monoclonal antibodies and carbohydrate blocking assays. Amino acid profiles from antigenic sites (A, C, D, E, and G) correlated with the circulation patterns of GII.4 variants, with three of them (A, C, and G) containing residues (352, 357, 368, and 378) linked with the diversifying selective pressure on the emergence of new GII.4 variants. Notably, the emergence of each variant was followed by stochastic diversification with minimal changes that did not progress toward the next variant. This report provides a methodological framework for antigenic characterization of viruses and expands our understanding of the dynamics of GII.4 noroviruses and could facilitate the design of cross-reactive vaccines.IMPORTANCE Noroviruses are an important cause of viral gastroenteritis around the world. An obstacle delaying the development of norovirus vaccines is inadequate understanding of the role of norovirus diversity in immunity. Using a population genomics approach, we identified new residues on the viral capsid protein (VP1) from GII.4 noroviruses, the predominant genotype, that appear to be involved in the emergence and antigenic topology of GII.4 variants. Careful monitoring of the substitutions in those residues involved in the diversification and emergence of new viruses could help in the early detection of future novel variants with pandemic potential. Therefore, this novel information on the antigenic diversification could facilitate GII.4 norovirus vaccine design.

SUBMITTER: Tohma K

PROVIDER: S-EPMC6759766 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:GII.2[P16] and GII.4 Sydney [P16] are currently the two predominant norovirus genotypes. This study sought to clarify their evolutionary patterns by analyzing the major capsid VP1 and RNA-dependent RNA polymerase (RdRp) genes. Sequence diversities were analyzed at both nucleotide and amino acid levels. Selective pressures were evaluated with the Hyphy package in different models. Phylogenetic trees were constructed by the maximum likelihood method from full VP1 sequences, and evolutionary rates were estimated by the Bayesian Markov Chain Monte Carlo approach. The results showed that (1) several groups of tightly linked mutations between the RdRp and VP1 genes were detected in the GII.2[P16] and GII.4[P16] noroviruses, and most of these mutations were synonymous, which may lead to a better viral fitness to the host; (2) although the pattern of having new GII.4 variants every 2-4 years has been broken, both the pre- and the post-2015 Sydney VP1 had comparable evolutionary rates to previously epidemic GII.4 variants, and half of the major antigenic sites on GII.4 Sydney had residue substitutions and several caused obvious changes in the carbohydrate-binding surface that may potentially alter the property of the virus; and (3) GII.4 Sydney variants during 2018-21 showed geographical specificity in East Asia, South Asia, and North America; the antigenic sites of GII.2 are strictly conserved, but the GII.2 VP1 chronologically evolved into nine different sublineages over time, with sublineage IX being the most prevalent one since 2018. This study suggested that both VP1 and RdRp of the GII.2[P16] and GII.4 Sydney [P16] noroviruses exhibited different evolutionary directions. GII.4[P16] is likely to generate potential novel epidemic variants by accumulating mutations in the P2 domain, similar to previously epidemic GII.4 variants, while GII.2[P16] has conserved predicted antigenicity and may evolve by changing the properties of nonstructural proteins, such as polymerase replicational fidelity and efficiency. This study expands the understanding of the evolutionary dynamics of GII.2[P16] and GII.4[P16] noroviruses and may predict the emergence of new variants.

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Population Genomics of GII.4 Noroviruses Reveal Complex Diversification and New Antigenic Sites Involved in the Emergence of Pandemic Strains.

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