Abstract

BackgroundEnterovirus 71 (EV71) has emerged as a neuroinvasive virus responsible for several large outbreaks in the Asia-Pacific region while virulence determinant remains unexplored.Principal FindingsIn this report, we investigated increased virulence of unadapted EV71 clinical isolate 237 as compared with isolate 4643 in mice. A fragment 12 nucleotides in length in stem loop (SL) II of 237 5′-untranslated region (UTR) visibly reduced survival time and rate in mice was identified by constructing a series of infectious clones harboring chimeric 5′-UTR. In cells transfected with bicistronic plasmids, and replicon RNAs, the 12-nt fragment of isolate 237 enhanced translational activities and accelerated replication of subgenomic EV71. Finally, single nucleotide change from cytosine to uridine at base 158 in this short fragment of 5′-UTR was proven to reduce viral translation and EV71 virulence in mice. Results collectively indicated a pivotal role of novel virulence determinant C158 on virus translation in vitro and EV71 virulence in vivo.ConclusionsThese results presented the first reported virulence determinant in EV71 5′-UTR and first position discovered from unadapted isolates.

Highlights

  • Enterovirus 71 (EV71), a member of the genus Enterovirus of Picornaviridae family, is a non-enveloped virus with positive, singlestranded RNA of about 7400 nt [1]

  • These results presented the first reported virulence determinant in EV71 59-untranslated region (UTR) and first position discovered from unadapted isolates

  • Six major stem loop (SL) structures essential to viral RNA replication [5] and translation [6,7] were identified within picornavirus 59-UTR [2,8]

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Summary

Introduction

Enterovirus 71 (EV71), a member of the genus Enterovirus of Picornaviridae family, is a non-enveloped virus with positive, singlestranded RNA of about 7400 nt [1]. Its viral genome encodes a large polyprotein with a single open reading frame (ORF) flanked by 59-untranslated region (UTR) and 39-UTR. Polyprotein divides into three regions [2]: P1 containing capsid proteins VP1, VP2, VP3 and VP4; P2 and P3 containing non-structural proteins (2A, 2B, 2C, 3A, 3B, 3C and 3D) crucial to virus replication. Genome translation is initiated by a cap-independent mechanism mediated by internal ribosome entry site (IRES) in highly structured 59UTR [3,4]. Six major stem loop (SL) structures essential to viral RNA replication [5] and translation [6,7] were identified within picornavirus 59-UTR [2,8]. Enterovirus 71 (EV71) has emerged as a neuroinvasive virus responsible for several large outbreaks in the AsiaPacific region while virulence determinant remains unexplored

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