Heparan sulfate attachment receptor is a major selection factor for attenuated enterovirus 71 mutants during cell culture adaptation

English version

Autoři: Kyousuke Kobayashi ^aff001; Katsumi Mizuta ^aff002; Satoshi Koike ^aff001
Působiště autorů: Neurovirology Project, Department of Genome Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan ^aff001; Department of Microbiology, Yamagata Prefectural Institute of Public Health, Yamagata, Japan ^aff002
Vyšlo v časopise: Heparan sulfate attachment receptor is a major selection factor for attenuated enterovirus 71 mutants during cell culture adaptation. PLoS Pathog 16(3): e1008428. doi:10.1371/journal.ppat.1008428
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008428

Souhrn

Enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease (HFMD). However, this infection is sometimes associated with severe neurological complications. Identification of neurovirulence determinants is important to understand the pathogenesis of EV71. One of the problems in evaluating EV71 virulence is that its genome sequence changes rapidly during replication in cultured cells. The factors that induce rapid mutations in the EV71 genome in cultured cells are unclear. Here, we illustrate the population dynamics during adaptation to RD-A cells using EV71 strains isolated from HFMD patients. We identified a reproducible amino acid substitution from glutamic acid (E) to glycine (G) or glutamine (Q) in residue 145 of the VP1 protein (VP1-145) after adaptation to RD-A cells, which was associated with attenuation in human scavenger receptor B2 transgenic (hSCARB2 tg) mice. Because previous reports demonstrated that VP1-145G and Q mutants efficiently infect cultured cells by binding to heparan sulfate (HS), we hypothesized that HS expressed on the cell surface is a major factor for this selection. Supporting this hypothesis, selection of the VP1-145 mutant was prevented by depletion of HS and overexpression of hSCARB2 in RD-A cells. In addition, this mutation promotes the acquisition of secondary amino acid substitutions at various positions of the EV71 capsid to increase its fitness in cultured cells. These results indicate that attachment receptors, especially HS, are important factors for selection of VP1-145 mutants and subsequent capsid mutations. Moreover, we offer an efficient method for isolation and propagation of EV71 virulent strains with minimal selection pressure for attenuation.

Klíčová slova:

Cell cultures – Mammalian genomics – Microbial mutation – Mutation detection – RNA viruses – Substitution mutation – Viral genomics – Viral replication

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