Abstract
Norovirus (NoV) is the major pathogen causing the outbreaks of the viral gastroenteritis across the world. Among the various genotypes of NoV, GII.4 is the most predominant over the past decades. GII.4 NoVs interact with the histo-blood group antigens (HBGAs) to invade the host cell, and it is believed that the receptor HBGAs may play important roles in selecting the predominate variants by the nature during the evolution of GII.4 NoVs. However, the evolution-induced changes in the HBGA-binding affinity for the GII.4 NoV variants and the mechanism behind the evolution of the NoV-HBGA interactions remain elusive. In the present work, the virus-like particles (VLPs) of the representative GII.4 NoV stains epidemic in the past decades were expressed by using the Hansenula polymorpha yeast expression platform constructed by our laboratory, and then the enzyme linked immunosorbent assay (ELISA)-based HBGA-binding assays as well as the molecular dynamics (MD) simulations combined with the molecular mechanics/generalized born surface area (MMGBSA) calculations were performed to investigate the interactions between various GII.4 strains and different types of HBGAs. The HBGA-binding assays show that for all the studied types of HBGAs, the evolution of GII.4 NoVs results in the increased NoV-HBGA binding affinities, where the early epidemic strains have the lower binding activity and the newly epidemic strains exhibit relative stronger binding intensity. Based on the MD simulation and MMGBSA calculation results, a physical mechanism that accounts for the increased HBGA-binding affinity was proposed. The evolution-involved residue mutations cause the conformational rearrangements of loop-2 (residues 390-396), which result in the narrowing of the receptor-binding pocket and thus tighten the binding of the receptor HBGAs. Our experimental and computational studies are helpful for better understanding the mechanism behind the evolution-induced increasing of HBGA-binding affinity, which may provide useful information for the drug and vaccine designs against GII.4 NoVs.
Highlights
Norovirus (NoV) is a highly infectious pathogen of human, which is responsible for most of the outbreaks of the viral gastroenteritis around the world
It has been revealed that the histo-blood group antigens (HBGAs) serve as the recognition receptor for the GII.4
NoVs infecting the host cell, and the NoV-HBGA interactions may play an important role in selecting the predominate variants during the evolution of GII.4
Summary
Norovirus (NoV) is a highly infectious pathogen of human, which is responsible for most of the outbreaks of the viral gastroenteritis around the world. NoV is highly genetically heterogenous and diverse, which can be grouped into seven genogroups, i.e., genogroup I (GI) to GVII [3, 4] Among these genogroups, GI, GII and GIV can infect human, each of which can be further divided into many genotypes [4]. NoV is the first strain that causes the NoV pandemic in human [7, 8]. In early 2006, the outbreaks of gastroenteritis in Australia, New Zealand and Europe were caused by the GII. variants termed as 2006a and 2006b strains [12]. In October 2009, a new GII. variant termed New Orleans was detected from the samples of NoV outbreaks in the United States, which predominated NoV spreads during 2009 to 2012 [15, 16].
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