Abstract
MicroRNAs (miRNAs) regulate virus replication through multiple mechanisms. Poliovirus causes a highly debilitating disease and though global efforts to eradicate polio have sharply decreased polio incidence, unfortunately three countries (Afghanistan, Nigeria and Pakistan) remain polio-endemic. We hypothesize that understanding the host factors involved in polio replication will identify novel prophylactic and therapeutic targets against polio and related viruses. In this data set, employing genome wide screens of miRNA mimics and inhibitors, we identified miRNAs which significantly suppressed polio replication. Specifically, miR-134 regulates poliovirus replication via modulation of ras-related nuclear protein (RAN), an important component of the nuclear transport system. MiR-134 also inhibited other Picornaviridae viruses including EV71, a growing concern and a high priority for vaccination in Asian countries like China. These findings demonstrate a novel mechanism for miRNA regulation of poliovirus and other Picornaviridae viruses in host cells, and thereby may provide a novel approach in combating infection and a potential approach for the development of anti-Picornaviridae strategies.
Highlights
Background and SummaryPoliovirus (PV), a non-enveloped human enterovirus virus of the Picornaviridae family is the etiological agent of poliomyelitis
Enterovirus 71 (EV71), a relative of PV, is a major public health burden in the Western Pacific region associated with severe neurologic symptoms of hand, foot and mouth disease (HFMD), a disease most often contracted by children o5 years old[3]
We investigated whether miRNA-transfection with miR-134 inhibited EV71 replication
Summary
Poliovirus (PV), a non-enveloped human enterovirus virus of the Picornaviridae family is the etiological agent of poliomyelitis (polio). HEp-2C cells were reverse-transfected with non-targeting siRNA, miRNA negative controls, or gene specific mimics for 48 h. MiRNA effects on Sabin-2 replication were evaluated by a PV type-II specific ELISA14,15. Mimics that resulted in a z-score ≤− 1.5 s.d. were deemed hits and subjected to validation experiments which utilized miRNA inhibitors targeting the same genes (Table 1). Ingenuity pathway analysis (IPA; QIAGEN) was utilized to evaluate protein networks associated with PV replication to predict targets of miR-134 that may be involved in PV replication. IPA and TargetScan analysis revealed many predicted targets, of interest was the nuclear transport system protein (RAN) because it miR-197 inhibited EV72 replication[16]. It is possible that miR-134 may regulate other host genes required for PV replication, which is supported by the evidence that one miRNA can regulate large numbers of target mRNAs17. These findings demonstrate miRNA regulation of PV and EV71 and may provide a novel approach in combating infection
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