Mutations in VP1 and 5\u2032-UTR affect enterovirus 71 virulence

Ching-Kun Chang,Shang-Rung Wu,Yen-Hung Chow,Nai-Hsiang Chung,Shu-Ling Yu,Ying-Chin Chen,Chia-Chyi Liu,Kuen-Jin Lee,Yi-Ju Lu

doi:10.1038/s41598-018-25091-7

Abstract

Enterovirus 71 (EV71) is a major cause of hand, foot and mouth disease (HFMD). The current EV71 propagating in Vero (EV-V) or sub-passaged in RD (EV-R) cells was used as a pathogen. Interestingly, EV-R exhibited differential virulence; challenging human scavenger receptor class B2-expressing (hSCARB2-Tg) mice with EV71 revealed that EV-V was more virulent than EV-R: 100% of mice that received lethal amounts of EV-V died, while all the mice that received EV-R survived. Severe pathogenesis correlated with viral burdens and proinflammatory cytokine levels were observed in EV-V-challenged mice, but controversy in EV-R-challenged mice. Consensus sequence analysis revealed EV-R rapidly acquired complete mutations at E145G and S241L and partial mutations at V146I of VP1, and acquired a T to C substitution at nucleotide 494 of the 5′-UTR. EV-R exhibited higher binding affinity for another EV71 receptor, human P-selectin glycoprotein ligand-1 (hPSGL-1), than EV-V. Both EV71s exhibited no significant difference in binding to hSCARB2. The molecular modelling indicate that these mutations might influence EV71 engagement with PSGL-1 and in vivo virulence.

Highlights

Enterovirus 71 (EV71) is a major cause of hand, foot and mouth disease (HFMD)
To evaluate the pathogenesis of EV71 in vivo, the C2 genotype of EV71 Tainan/5746/98 was cultured in Vero cells (EV-V), or viral seeds were passaged in RD cells to generate EV-R pathogens (Supplementary Table S3)
The pictures indicated the cytopathic effect of EV71 propagating in Vero (EV-V) vs. EV-R in each passage were no significant difference (Supplementary Table S3). human scavenger receptor class B 2 (hSCARB2)-Tg mice on a C57BL/6 background were shown to be an experimental model that develops HFMD-like disease after infection with the B2 and C2 genotypes of EV71, with severe CNS pathology leading to death[14]

Summary

Introduction

Enterovirus 71 (EV71) is a major cause of hand, foot and mouth disease (HFMD). The current EV71 propagating in Vero (EV-V) or sub-passaged in RD (EV-R) cells was used as a pathogen. EV-R exhibited higher binding affinity for another EV71 receptor, human P-selectin glycoprotein ligand-1 (hPSGL-1), than EV-V. Its single open reading frame codes for a polyprotein that contains three regions, P1, P2 and P3 When it infects cells, the P1 precursor, which is encoded by the P1 region, is cleaved by the protease into VP1, VP2, VP3 and VP4; VP1, VP2, and VP3 are exposed on the surface of virions that are responsible for host-receptor binding[6]. The passage of isolated virus in animals and cell cultures may induce mutations that alter viral virulence or tropism[15]. V123 in VP1generate resistance to two novel capsid-binding compounds, the pyridyl imidazolidinones analogues NLD and ALD, during serial passage of EV7128

Methods

Results

Conclusion