A decade of sustained selection pressure on two surface sites of the VP1 protein of Enterovirus A71 suggests that immune evasion may be an indirect driver for virulence

Abstract

Enterovirus A71 (EV-A71) is an emerging pathogen in the Enterovirus A species group. EV-A71 causes hand, foot and mouth disease (HFMD), with virulent variants exhibiting polio-like acute flaccid paralysis and other central nervous system manifestations. We analysed all enterovirus A71 complete genomes with collection dates from 2008 to mid-2018. All sub-genotypes exhibit a strong molecular clock with omega (dN/dS) suggesting strong purifying selection. In sub-genotypes B5 and C4, positive selection can be detected at two surface sites on the VP1 protein, also detected in positive selection studies performed prior to 2008. Toggling of a limited repertoire of amino acids at these positively selected residues over the last decade suggests that EV-A71 may be undergoing a sustained frequency-dependent selection process for immune evasion, raising issues for vaccine development. These same sites have also been previously implicated in virus-host binding and strain-associated severity of HFMD, suggesting that immune evasion may be an indirect driver for virulence (154 words).

Unveiling of Evolution Pattern for HY12 Enterovirus Quasispecies and Pathogenicity Alteration

“…With the increase of the passages, the diversity of HY12 quasispecies increased, while the mutation rates and the complexity for HY12 quasispecies decreased. These results were consistent with the evolution pattern for many RNA viruses and were likely beneficial for HY12 virus survival [1]. As a driving force for evolution, mutations revealed for HY12 virus in the progress of virus passages are likely the mechanism for the virus adapt to different environments and produce high adaptability, which is also evidenced by the positive natural selection revealed for the VP1 protein in this study.…”

“…Virus uses different strategies to survive the changeable environments. Enterovirus, like the majority of RNA viruses, employs the strategies of mutation to adapt the surroundings and implicate in pathogenesis [1][2][3][4]. As an important causative agent, enterovirus is a member of the genus of Enterovirus within the family of Picornaviridae.…”

A tradeoff between enterovirus A71 particle stability and cell entry

“…These results suggest a possible mechanism underlying the increase of K162E in neurovirulence 50 . It was recently proposed that increased attachment to SCARB2 and a decrease of interaction with heparin sulfate is associated with an increased EV-A71 neurovirulence 51,50,52,53 . Thus, the isolated thermostable virus is more pathogenic regardless of the fact that in cell culture demonstrated reduced entry e ciency.…”

A tradeoff between enterovirus A71 particle stability and cell entry

“…These results suggest a possible mechanism underlying the increase of K162E in neurovirulence 50 . It was recently proposed that increased attachment to SCARB2 and a decrease of interaction with heparin sulfate is associated with an increased EV-A71 neurovirulence 51,50,52,53 . Thus, the isolated thermostable virus is more pathogenic regardless of the fact that in cell culture demonstrated reduced entry efficiency.…”