Serum MicroRNA Expression Profile Distinguishes Enterovirus 71 and Coxsackievirus 16 Infections in Patients with Hand-Foot-and-Mouth Disease

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微生物感染患者已被证实存在循环微RNA（microRNA, miRNA）表达谱异常。本研究对比了肠道病毒71型（EV71）、柯萨奇病毒16型（CVA16）引发的手足口病（HFMD）患者、其他微生物感染患者及健康个体的血清miRNA水平。通过微RNA芯片对664种不同miRNA进行检测后发现，肠道病毒感染患者的血清中存在102种上调miRNA与26种下调miRNA。随后采用实时定量聚合酶链反应（qRT-PCR）对10种候选miRNA的表达水平开展验证实验。受试者工作特征（ROC）曲线分析结果显示，6种miRNA（miR-148a、miR-143、miR-324-3p、miR-628-3p、miR-140-5p及miR-362-3p）能够有效区分肠道病毒感染患者与健康对照个体，其曲线下面积（AUC）介于0.828至0.934之间。通过多元逻辑回归分析联合该6种miRNA，不仅实现了97.1%的灵敏度与92.7%的特异度，还可构建独特的表达谱以区分肠道病毒感染与其他微生物感染。相较于EV71感染患者，CVA16感染患者体内5种miRNA（miR-148a、miR-143、miR-324-3p、miR-545及miR-140-5p）的表达水平显著升高（p