Abstract
Human norovirus (HuNoV) is the leading cause of nonbacterial gastroenteritis worldwide with the GII.4 genotype accounting for over 80% of infections. The major capsid protein of GII.4 variants is evolving rapidly, resulting in new epidemic variants with altered antigenic potentials that must be considered for the development of an effective vaccine. In this study, we identify and characterize linear blockade B-cell epitopes in HuNoV GII.4. Five unique linear B-cell epitopes, namely P2A, P2B, P2C, P2D, and P2E, were predicted on the surface-exposed regions of the capsid protein. Evolving of the surface-exposed epitopes over time was found to correlate with the emergence of new GII.4 outbreak variants. Molecular dynamic simulation (MD) analysis and molecular docking revealed that amino acid substitutions in the putative epitopes P2B, P2C, and P2D could be associated with immune escape and the appearance of new GII.4 variants by affecting solvent accessibility and flexibility of the antigenic sites and histo-blood group antigens (HBAG) binding. Testing the synthetic peptides in wild-type mice, epitopes P2B (336–355), P2C (367–384), and P2D (390–400) were recognized as GII.4-specific linear blockade epitopes with the blocking rate of 68, 55 and 28%, respectively. Blocking rate was found to increase to 80% using the pooled serum of epitopes P2B and P2C. These data provide a strategy for expanding the broad blockade potential of vaccines for prevention of NoV infection.
Highlights
Noroviruses cause most of acute gastroenteritis cases in children and adults worldwide [1]
To figure out how these epitopes evolve over time, amino acid multiple alignments of GII.4 capsid protein consensus sequences spanning the years 1987 to 2016, and the sequence of the major outbreaks in 1987, 1997, 2002, 2004, 2006, 2009, and 2012 were generated
We propose a model of antigenic evolution for GII-4 NoV strains based on sequence diversity, structural modelling and dynamic evolution of these surface-exposed antigenic regions over time
Summary
Noroviruses cause most of acute gastroenteritis cases in children and adults worldwide [1]. According to recently published reports, norovirus causes 685 million cases of cute gastroenteritis every year, resulting in a total cost of about $60 billion worldwide [2,3,4]. New antigenic variants emerge from the GII. lineage every 2–3 years and are often associated with widespread outbreaks [13]. This diversity poses potential challenges in development of a protective vaccine. The study of neutralization antibodies and epitopes is restricted by the lack of cell culture and animal models for HuNoV cultivation
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