Serum microRNA expression profile distinguishes enterovirus 71 and coxsackievirus 16 infections in patients with hand-foot-and-mouth disease.

Lunbiao Cui,Minghao Zhou,Yiyue Ge,Zhiyang Shi,Xiling Guo,Yuhua Qi,Yan Guo,Hua Wang,Kangchen Zhao,Baoli Zhu,Haijing Li,Jun Li,Charles W Stratton,Yi-Wei Tang,Xian Qi,Dong-Yan Jin

doi:10.1371/journal.pone.0027071

Abstract

Altered circulating microRNA (miRNA) profiles have been noted in patients with microbial infections. We compared host serum miRNA levels in patients with hand-foot-and-mouth disease (HFMD) caused by enterovirus 71 (EV71) and coxsackievirus 16 (CVA16) as well as in other microbial infections and in healthy individuals. Among 664 different miRNAs analyzed using a miRNA array, 102 were up-regulated and 26 were down-regulated in sera of patients with enteroviral infections. Expression levels of ten candidate miRNAs were further evaluated by quantitative real-time PCR assays. A receiver operating characteristic (ROC) curve analysis revealed that six miRNAs (miR-148a, miR-143, miR-324-3p, miR-628-3p, miR-140-5p, and miR-362-3p) were able to discriminate patients with enterovirus infections from healthy controls with area under curve (AUC) values ranged from 0.828 to 0.934. The combined six miRNA using multiple logistic regression analysis provided not only a sensitivity of 97.1% and a specificity of 92.7% but also a unique profile that differentiated enterovirial infections from other microbial infections. Expression levels of five miRNAs (miR-148a, miR-143, miR-324-3p, miR-545, and miR-140-5p) were significantly increased in patients with CVA16 versus those with EV71 (p<0.05). Combination of miR-545, miR-324-3p, and miR-143 possessed a moderate ability to discrimination between CVA16 and EV71 with an AUC value of 0.761. These data indicate that sera from patients with different subtypes of enteroviral infection express unique miRNA profiles. Serum miRNA expression profiles may provide supplemental biomarkers for diagnosing and subtyping enteroviral HFMD infections.

Highlights

More than 500,000 hand-foot-and-mouth disease (HFMD) cases including 176 fatal cases have been reported occurred in China since March 2008 [1]
We evaluated serum miRNA expression levels following enteroviral infections, and whether these changes could be used to assist in detection these infections as well as discrimination of specific enteroviral subtypes causing these infections
There were no significant differences in age and gender distributions among enterovirus 71 (EV71)- and coxsackievirus A16 (CVA16)-infected patients and healthy children (Table S1)

Summary

Introduction

More than 500,000 hand-foot-and-mouth disease (HFMD) cases including 176 fatal cases have been reported occurred in China since March 2008 [1]. Human enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) were the two major causative agents of HFMD accounting for more than 70% of cases in recent outbreaks [2]. Cellular development and differentiation, oncogenesis, and host transcription and translation are modified during enteroviral infections [3]. Several transcription factors such as E2F transcription factor 1, EIF3S9, and EIF2B5, are down-regulated early in the infection and up-regulated later in the infection [3]. Other genes encoding antigen presentation molecules, immune cell activation markers, chemokines, and interferon (IFN)-inducible gene products are known to be modulated in response to viral infections [3,4]

Methods

Results

Conclusion