MiR-16-5p mediates a positive feedback loop in EV71-induced apoptosis and suppresses virus replication

Caishang Zheng, Zhenhua Zheng, Jianhong Sun, Yuan Zhang, Chunyu Wei, Xianliang Ke, Yan Liu, Li Deng, Hanzhong Wang
2017 Scientific Reports  
Enterovirus 71 (EV71) is the predominant causative pathogen of hand-foot-and-mouth disease (HFMD). Contrary to other HFMD-causing enterovirus, EV71 can lead to severe neurological complications, even death. MicroRNAs (miRNAs) are small non-coding RNAs that constitute the largest family of gene regulators participating in numerous biological or pathological processes. We previously reported that miR-16-5p increases with severity of HFMD by investigating the expression patterns of host miRNAs in
more » ... atients with HFMD. However, the mechanisms by which EV71 induces miR-16-5p expression are not clear, and the interaction between EV71 and miR-16-5p is not yet fully understood. Here, we confirmed EV71-induced expression of miR-16-5p both in vitro and in vivo and show that upregulation of miR-16-5p by EV71 infection may occur at the posttranscriptional level. Moreover, EV71-induced caspase activation facilitates the processing of pri-miR-16-1. We also revealed that miR-16-5p can promote EV71-induced nerve cells apoptosis through activating caspase-3. In addition, we found that miR-16-5p can inhibit EV71 replication. CCNE1 and CCND1, two important cell cycle regulators, play an important role in the suppression of EV71 replication by miR-16-5p. Therefore, miR-16-5p is a positive feedback regulator in EV71-induced apoptosis and a suppressor of virus replication. These results help in understanding the interaction network between miRNA and EV71 infection and provide a potential target for the development of antiviral therapy. Enterovirus 71 (EV71) is a single-positive-stranded RNA virus belonging to the Enterovirus genus of the Picornaviridae family 1,2 . EV71 is identified as one of the causative pathogens of infant hand-foot-and-mouth disease (HFMD) and transmitted through faecal-oral and respiratory routes 3 . Although HFMD is generally asymptomatic or presents benign symptoms, the disease may also lead to severe neurological complications 4,5 . Similar to poliovirus, acute EV71 infection can cause severe neurological complications, including myocarditis, aseptic meningitis, encephalitis, acute flaccid paralysis, pulmonary oedema or haemorrhage and even fatality 1,6-8 . Children under five years old are the mainly susceptible to severe EV71 infection 9 . Since being first reported in 1974, EV71 has induced several epidemic outbreaks in the world, particularly in the Asia-Pacific region 10-12 . However, specific antiviral therapies for the treatment of HFMD patients are currently unavailable because of high genomic mutation rate and lack of understanding on EV71 pathogenesis 13 . The underlying mechanisms through which EV71 infection induces serious cerebral and pulmonary complications and even death are unclear 14 . Therefore, further investigation on the pathogenesis of EV71 infection has kindled considerable research interest in the field of medicine and biology. MicroRNAs (miRNAs) are approximately 19-24 nt non-coding RNAs that post-transcriptionally repress gene expression by targeting messenger RNAs (mRNAs) 15,16 . MiRNAs were firstly identified in Caenorhabditis elegans and are widely expressed in vertebrates, plants and several DNA viruses 15,17 . To date, >5500 miRNAs have been predicted throughout the human genome with numerous limited to specific tissues 18, 19 . A total of 28645 miRNA have been annotated in the current version of the miRNA database (the miRBase Sequence Database-Release 21).
doi:10.1038/s41598-017-16616-7 pmid:29180670 pmcid:PMC5703983 fatcat:4mgpnrrpenbzddkelxkfm4mcfy