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Antigenic cartography reveals complexities of genetic determinants that lead to antigenic differences among pandemic GII.4 noroviruses.

ABSTRACT: Noroviruses are the predominant cause of acute gastroenteritis, with a single genotype (GII.4) responsible for the majority of infections. This prevalence is characterized by the periodic emergence of new variants that present substitutions at antigenic sites of the major structural protein (VP1), facilitating escape from herd immunity. Notably, the contribution of intravariant mutations to changes in antigenic properties is unknown. We performed a comprehensive antigenic analysis on a virus-like particle panel representing major chronological GII.4 variants to investigate diversification at the inter- and intravariant level. Immunoassays, neutralization data, and cartography analyses showed antigenic similarities between phylogenetically related variants, with major switches to antigenic properties observed over the evolution of GII.4 variants. Genetic analysis indicated that multiple coevolving amino acid changes-primarily at antigenic sites-are associated with the antigenic diversification of GII.4 variants. These data highlight complexities of the genetic determinants and provide a framework for the antigenic characterization of emerging GII.4 noroviruses.

SUBMITTER: Kendra JA

PROVIDER: S-EPMC7980451 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Antigenic cartography reveals complexities of genetic determinants that lead to antigenic differences among pandemic GII.4 noroviruses.

Kendra Joseph A JA Tohma Kentaro K Ford-Siltz Lauren A LA Lepore Cara J CJ Parra Gabriel I GI

Proceedings of the National Academy of Sciences of the United States of America 20210301 11

Noroviruses are the predominant cause of acute gastroenteritis, with a single genotype (GII.4) responsible for the majority of infections. This prevalence is characterized by the periodic emergence of new variants that present substitutions at antigenic sites of the major structural protein (VP1), facilitating escape from herd immunity. Notably, the contribution of intravariant mutations to changes in antigenic properties is unknown. We performed a comprehensive antigenic analysis on a virus-lik ...[more]

PMID: 33836574

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Project description: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.

Project description:LC-MS/MS proteomics analysis (Ig-Seq) of human sera collected before and after GII.4 monovalent oral HuNoV vaccination. Here is a brief description of MS files: VX101-160 day29 FT_2MUrea PF8302 8302_JP_1a_psms.txt 8302_JP_1a.raw VX101-160 day29 FT_2MUrea PF8302 8302_JP_1b_psms.txt 8302_JP_1b.raw VX101-160 day29 FT_2MUrea PF8302 8302_JP_1c_psms.txt 8302_JP_1c.raw VX101-160 day29 Elu_2MUrea PF8302 8302_JP_2a_psms.txt 8302_JP_2a.raw VX101-160 day29 Elu_2MUrea PF8302 8302_JP_2b_psms.txt 8302_JP_2b.raw VX101-160 day29 Elu_2MUrea PF8302 8302_JP_2c_psms.txt 8302_JP_2c.raw VX101-160 day1 FT PF8286 8286_1a_psms.txt 8286_1a.raw VX101-160 day1 FT PF8286 8286_1b_psms.txt 8286_1b.raw VX101-160 day1 FT PF8286 8286_1c_psms.txt 8286_1c.raw VX101-160 day1 Elu PF8286 8286_2a_psms.txt 8286_2a.raw VX101-160 day1 Elu PF8286 8286_2b_psms.txt 8286_2b.raw VX101-160 day1 Elu PF8286 8286_2c_psms.txt 8286_2c.raw VX101-003 day29 G11_FT PF8507 8507_1a_psms.txt 8507_1a.raw VX101-003 day29 G11_FT PF8507 8507_1b_psms.txt 8507_1b.raw VX101-003 day29 G11_FT PF8507 8507_1c_psms.txt 8507_1c.raw VX101-003 day29 G11_Elu PF8507 8507_2a_psms.txt 8507_2a.raw VX101-003 day29 G11_Elu PF8507 8507_2b_psms.txt 8507_2b.raw VX101-003 day29 G11_Elu PF8507 8507_2c_psms.txt 8507_2c.raw VX101-003 day29 G23_FT PF8507 8507_3a_psms.txt 8507_3a.raw VX101-003 day29 G23_FT PF8507 8507_3b_psms.txt 8507_3b.raw VX101-003 day29 G23_FT PF8507 8507_3c_psms.txt 8507_3c.raw VX101-003 day29 G23_Elu PF8507 8507_4a_psms.txt 8507_4a.raw VX101-003 day29 G23_Elu PF8507 8507_4b_psms.txt 8507_4b.raw VX101-003 day29 G23_Elu PF8507 8507_4c_psms.txt 8507_4c.raw VX101-003 day29 G24_FT PF8507 8507_5a_psms.txt 8507_5a.raw VX101-003 day29 G24_FT PF8507 8507_5b_psms.txt 8507_5b.raw VX101-003 day29 G24_FT PF8507 8507_5c_psms.txt 8507_5c.raw VX101-003 day29 G24_Elu PF8507 8507_6a_psms.txt 8507_6a.raw VX101-003 day29 G24_Elu PF8507 8507_6b_psms.txt 8507_6b.raw VX101-003 day29 G24_Elu PF8507 8507_6c_psms.txt 8507_6c.raw VX101-003 day1 G11_FT PF8521 8521_1a_psms.txt 8521_1a.raw VX101-003 day1 G11_FT PF8521 8521_1b_psms.txt 8521_1b.raw VX101-003 day1 G11_FT PF8521 8521_1c_psms.txt 8521_1c.raw VX101-003 day1 G11_Elu PF8521 8521_2a_psms.txt 8521_2a.raw VX101-003 day1 G11_Elu PF8521 8521_2b_psms.txt 8521_2b.raw VX101-003 day1 G11_Elu PF8521 8521_2c_psms.txt 8521_2c.raw VX101-003 day1 G23_FT PF8521 8521_3a_psms.txt 8521_3a.raw VX101-003 day1 G23_FT PF8521 8521_3b_psms.txt 8521_3b.raw VX101-003 day1 G23_FT PF8521 8521_3c_psms.txt 8521_3c.raw VX101-003 day1 G23_Elu PF8521 8521_4a_psms.txt 8521_4a.raw VX101-003 day1 G23_Elu PF8521 8521_4b_psms.txt 8521_4b.raw VX101-003 day1 G23_Elu PF8521 8521_4c_psms.txt 8521_4c.raw VX101-003 day1 G24_FT PF8521 8521_5a_psms.txt 8521_5a.raw VX101-003 day1 G24_FT PF8521 8521_5b_psms.txt 8521_5b.raw VX101-003 day1 G24_FT PF8521 8521_5c_psms.txt 8521_5c.raw VX101-003 day1 G24_Elu PF8521 8521_6a_psms.txt 8521_6a.raw VX101-003 day1 G24_Elu PF8521 8521_6b_psms.txt 8521_6b.raw VX101-003 day1 G24_Elu PF8521 8521_6c_psms.txt 8521_6c.raw

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Antigenic cartography reveals complexities of genetic determinants that lead to antigenic differences among pandemic GII.4 noroviruses.

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Antigenic cartography reveals complexities of genetic determinants that lead to antigenic differences among pandemic GII.4 noroviruses.

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