[1]周延,雷芳,杨阳,等.儿童手足口病患者EV-71和Cox-A16感染与血清miRNA谱特征的相关性研究[J].现代检验医学杂志,2026,41(05):20-25.[doi:10.3969/j.issn.1671-7414.2026.05.004]
　ZHOU Yan,LEI Fang,YANG Yang,et al.Study on the Correlation of EV-71 and Cox-A16 Infections with Serum miRNA Profiles in Pediatric Hand-Foot-and-Mouth Disease[J].Journal of Modern Laboratory Medicine,2026,41(05):20-25.[doi:10.3969/j.issn.1671-7414.2026.05.004]
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儿童手足口病患者EV-71和Cox-A16感染与血清miRNA谱特征的相关性研究()

《现代检验医学杂志》[ISSN:/CN:]

卷:
第41卷
期数:
2026年05期
页码:
20-25
栏目:
论著
出版日期:
2026-09-15

文章信息/Info

Title:
Study on the Correlation of EV-71 and Cox-A16 Infections with Serum miRNA Profiles in Pediatric Hand-Foot-and-Mouth Disease
文章编号:
1671-7414 （2026） 05-020-06
作者:
周延，雷芳，杨阳，陈岑，王廷婷
（重庆医科大学附属大足医院儿科，重庆402360）
Author(s):
ZHOU Yan, LEI Fang, YANG Yang, CHEN Cen, WANG Tingting
(Department of Pediatrics, Chongqing Medical University Affiliated Dazu Hospital, Chongqing 402360, China)
关键词:
手足口病;  肠道病毒71型;  柯萨奇病毒A组16型;  儿童患者;  微小核糖核酸
分类号:
R725.1； R373.25； Q52； Q503
DOI:
10.3969/j.issn.1671-7414.2026.05.004
文献标志码:
A
摘要:
目的 分析儿童手足口病 （HFMD） 患者肠道病毒71型 （EV-71） 或柯萨奇病毒A组16型 （Cox-A16） 感染的血清微小核 糖核酸 （miRNA） 谱， 并探讨其临床意义。 方法 采用简单随机抽样法， 选取2023年11月~2024年8月在重庆医科大学附属大 足医院儿科确诊的儿童HFMD患者。 发现集包含EV-71或Cox-A16单一感染患儿各8例， 采用miRNA微阵列筛选差异表达 miRNA， 并进行生物信息学分析； 验证集包含Cox-A16组、 EV-71组以及健康对照组各105例， 采用实时荧光定量聚合酶链反 应法检测血清miRNA水平。 使用受试者操作特征 （ROC） 曲线开发基于miRNA的诊断模型。 结果 通过发现集筛选， 识别5个 差异表达miRNA （miR-21、 miR-143、 miR-494、 miR-146a、 miR-221） ， 基因本体论和京都基因和基因组百科全书通路富集证实 了这些差异表达miRNA与多种免疫相关通路有关。 在验证集中， EV-71组和Cox-A16组患儿血清miR-21、 miR-143、 miR-494、 miR-146a、 miR-221水平均显著高于健康对照组， 差异具有统计学意义 （H=7.714～100.551， 均P＜0.05） ， 且EV-71组血清miR- 21、 miR-494、 miR-143、 miR-146a水平高于Cox-A16组 （Z=-37.215～-9.443， 均P＜0.05） 。 调整年龄等临床变量后， miR-21、 miR-494、 miR-143、 miR-221、 miR-146a水平升高仍然与HFMD发病显著相关 （HR=1.104～1.400， 均P＜0.05） 。5种miRNA具 有诊断HFMD的能力， ROC曲线下面积 （AUC） 为0.584～0.874。miR-21、 miR-494、 miR-146a的组合具有区分诊断EV-71或 Cox-A16单一病毒亚型感染的能力， AUC为0.874。 结论 儿童HFMD患者存在特异性血清miRNA谱， 其中3种miRNA组合 模型具有区分EV-71或Cox-A16单一亚型感染的能力。
Abstract:
Objective To characterize the serum microRNA (miRNA) profile in pediatric hand-foot-and-mouth disease (HFMD) caused by Enterovirus 71 (EV-71) or Coxsackievirus group A type 16 (Cox-A16), and to analyze its clinical significance. Meth- ods Using a simple random sampling method, pediatric HFMD patients diagnosed at the Department of Pediatrics of Dazu Hos- pital Affiliated to Chongqing Medical University from November 2023 to August 2024 were enrolled. The discovery set included 8 children with EV-71 infection, and 8 with Cox-A16 infection. miRNA microarray was performed to screen for differentially expressed miRNAs. And the candidate miRNAs were analyzed by bioinformatics analysis. The validation set included Cox-A16 group, EV-71 group and healthy control group with 105 cases in each group. Serum miRNA levels were detected using real-time fluorescence quantitative polymerase chain reaction. Receiver operating characteristic (ROC) curves were used to develop a miR- NA-based diagnostic model. Results In the discovery set, ?ve differentially expressed miRNAs (miR-21, miR-143, miR-494, miR- 146a, and miR-221) were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment anal- ysis confirmed that these differentially expressed miRNAs were involved in multiple immune-related pathways. In the validation set, serum levels of miR-21, miR-143, miR-494, miR-146a, and miR-221 were significantly higher in both EV-71 and Cox-A16 groups than in healthy controls (H=7.714~100.551, all P ＜ 0.05), and serum levels of miR-21, miR-494, miR-143, and miR- 146a were significantly higher in the EV-71 group than the Cox-A16 group (Z=-37.215 to -9.443, all P ＜ 0.05). After adjusting for clinical variables including age, elevated levels of miR-21, miR-494, miR-143, miR-221, and miR-1466 remained significant- ly associated with the onset of HFMD (HR =1.104~1.400, all P ＜ 0.05). The ?ve-miRNA panel showed diagnostic capability for HFMD with an area under ROC curve (AUC) values ranging from 0.584 to 0.874. Moreover, the combination of miR-21, miR-494, and miR-146a demonstrated the ability to differentiate between EV-71 and Cox-A16 single-virus subtype infections, with AUC 0.874. Conclusions Pediatric HFMD has a speci?c serum miRNA pro?le, and the three-miRNA panel (miR-21, miR-494, and miR-146a) shows potential for distinguishing EV-71 from Cox-A16 infections.

参考文献/References:

[1] ZHANG X L, ZHANG Y F, LI H, et al. Hand-foot-and- mouth disease-associated enterovirus and the develop- ment of multivalent HFMD vaccines[J]. International Journal of Molecular Sciences, 2022, 24(1): 169.
[2] LI Y, YANG J M, LIANG L, et al. Clinical character- istics and severity of hand, foot, and mouth disease by virus serotype: a prospective hospital-based cohort study[J]. PLOS Neglected Tropical Diseases, 2025, 19(5): e0013039.
[3] XIA M Y, ZHU Y, LIAO J, et al. Clinical, aetiological, and epidemiological studies of outpatient cases of hand, foot, and mouth disease in Chengdu, China, from 2019 to 2022: a retrospective study[J]. BMC Public Health, 2024, 24(1): 3427.
[4] 潘虹 , 陈小玲 , 文奇 , 等 . 2018-2023 年新余地区手 足口病流行特征及其 CVA6 型病毒分子特征研究 [J]. 病毒学报 , 2025, 41(3): 645-651. PAN H, CHEN X L, WEN Q, et al. Analysis of epide- miological characteristics of HFMD and molecular fea- tures of CVA6 in Xinyu from 2018 to 2023[J]. Chinese Journal of Virology, 2025, 41(3): 645-651.
[5] CHOOI W H, WINANTO, ZENG Y, et al. Enterovi- rus-A71 preferentially infects and replicates in human motor neurons, inducing neurodegeneration by fer- roptosis[J]. Emerging Microbes & Infections, 2024, 13(1): Article: 2382235.
[6] SUN Y H, QIAN S S, DU Y X, et al. A single amino acid mutation in VP1 of coxsackievirus A6 determining e?ciency of VP0 cleavage and proliferation[J]. Journal of Virology, 2025, 99(6): e0012825.
[7] CHEN W, LI J W, LI J, et al. Roles of non-coding RNAs in virus-host interaction about pathogenesis of hand-foot-mouth disease[J]. Current Microbiology, 2022, 79(9): 247.
[8] ZHU P Y, CHEN S Y, ZHANG W G, et al. Essential role of non-coding RNAs in enterovirus infection: from basic mechanisms to clinical prospects[J]. International Journal of Molecular Sciences, 2021, 22(6): 2904.
[9] LIU G, ZHU D, FENG K, et al. The neurological dam- age caused by enterovirus 71 infection is associated with hsa_circ_0069335/miR-29b/PMP22 pathway [J]. Journal of Virology, 2025, 99(1): e0084424.
[10] 《手足口病诊疗指南 (2018 版)》 编写专家委员会 . 手 足口病诊疗指南 (2018 年版) [J]. 中华传染病杂志 , 2018, 36(5): 257-263. Expert Committee for Guidelines for the diagnosis and treatment of hand, foot, and mouth disease (2018 Edition). Guidelines for the diagnosis and treatment of hand, foot, and mouth disease (2018 Edition)[J]. Chinese Journal of Infectious Diseases, 2018, 36(5): 257-263.
[11] 朱磊 , 徐妍妍 , 盛利平 , 等 . 手足口病患儿血清 FGF- 21 与 GDF-15 水平检测的临床诊疗应用研究 [J]. 现 代检验医学杂志 , 2023, 38(5): 180-184. ZHU L, XU Y Y, SHENG L P, et al. Research on the application of serum FGF-21 and GDF-15 in clinical diagnosis and treatment of children with hand, foot and mouth disease[J]. Journal of Modern Laboratory Medi- cine, 2023, 38(5): 180-184.
[12] 张颖 , 秦红 , 刘凤霞 , 等 . 手足口病患儿血清 LTB4 和 COX2 水平表达与疾病严重程度及预后的相关性 研究 [J]. 现代检验医学杂志 , 2022, 37(5): 143-147. ZHANG Y, QIN H, LIU F X, et al. Correlation between serum LTB4 and COX-2 levels expression and disease severity, prognosis in children with hand-foot-and- mouth disease[J]. Journal of Modern Laboratory Medi- cine, 2022, 37(5): 143-147.
[13] SHRESTHA S, MALLA B, HARAMOTO E. Moni- toring hand foot and mouth disease using long-term wastewater surveillance in Japan: quantitative PCR as- say development and application[J]. Sci Total Environ, 2023, 901: 165926.
[14] 朱义芳 , 孙照华 , 蔡晶娟 , 等 .IgM 胶体金法与 RT- PCR 法对手足口病诊断及随访的价值分析 [J]. 四川 医学 , 2021, 42(2): 123-126. ZHU Y F, SUN Z H, CAI J J, et al. Value of IgM col- loidal gold method and RT-PCR method in diagnosis and follow-up of hand-foot-mouth disease[J]. Sichuan Medical Journal, 2021, 42(2): 123-126.
[15] HUANG C Y, SU S B, CHEN K T. A review of en- terovirus-associated hand-foot and mouth disease: pre- ventive strategies and the need for a global enterovirus surveillance network[J]. Pathogens and Global Health, 2024, 118(8): 538-548.
[16] TIAN X Y, LIU B X, LI L R, et al. Microvesicles car- rying EV71 virions cross BBB through endocytic path- way to induce brain injury[J]. Cell Communication and Signaling, 2025, 23(1): 183.
[17] FU L, ZHANG X Y, JIN W P, et al. Identi?cation of a conserved, linear epitope on VP3 of enterovirus a spe- cies recognized by a broad-spectrum monoclonal anti- body[J]. Viruses, 2023, 15(4): 1028.
[18] PIERI M, VAYIANOS P, NICOLAIDOU V, et al. Alter- ations in circulating miRNA levels after infection with SARS-CoV-2 could contribute to the development of car- diovascular diseases: what we know so far[J]. Internation- al Journal of Molecular Sciences, 2023, 24(3): 2380.
[19] CAVALLONE D, ORNOS E D B, RICCO G, et al. The circulating miRNA pro?le of chronic hepatitis D and B patients is comparable but differs from that of individ- uals with HBeAg-negative HBV infection[J]. Viruses, 2023, 15(11): 2257.
[20] WANG L L, WANG H, LIU T J, et al. METTL3-me- diated m6A modi?cation of circCSDE1 promote Cox- sackievirus replication by regulating the miR-891b/ BAG3 axis[J]. International Immunopharmacology, 2025, 159: 114905.
[21] TANG C Y, CHEN Y, JIN H J, et al. MiR-342-5p targets CTNNBIP1 to promote enterovirus 71 replica- tion[J]. Microbial Pathogenesis, 2023, 182: 106259.
[22] FENG N, ZHOU Z Z, LI Y X, et al. Enterovirus 71-in- duced has-miR-21 contributes to evasion of host im- mune system by targeting MyD88 and IRAK1[J]. Virus Research, 2017, 237: 27-36.
[23] LIU J, LU X C, ZHOU W D. Elevated circulating miR- 494 in plasma of children with enterovirus 71 induced hand, foot, and mouth disease and its potential diagnos- tic value[J]. Acta Virologica, 2020, 64(3): 338-343.
[24] WANG Y X, SHAO L J, ZHAO Z G, et al. Simultane- ous detection of dual microRNAs related to EV71 us- ing ICP-MS based on metal nanoparticle labeling with hybridization chain reaction[J]. Anal Chim Acta, 2024, 1294: 342272.
[25] YANG W X, LI L, LI G L, et al. Blocking CCL3-me- diated neutrophil recruitment into the brain alleviates immunopathology following severe enterovirus 71 in- fection[J]. iScience, 2024, 27(12): 111388.
[26] GUO H Z, ZHU Y Y, ZOU Y, et al. Enterovirus 71 in- duces pyroptosis of human neuroblastoma SH-SY5Y cells through miR-146a/ CXCR4 axis[J]. Heliyon, 2023, 9(4): e15014.

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备注/Memo

备注/Memo:
基金项目：重庆市科技发展项目（DZKJ2022JSYJ-KWXM1031）。
作者简介：周延（1989-），男，本科，主治医师，研究方向：重症肺炎的诊疗，E-mail：18523489876@163.com。
通讯作者：王廷婷（1990-），女，本科，主治医师，研究方向：手足口病、重症支气管肺炎的诊疗，E-mail：m15310663372@163.com。
更新日期/Last Update: 2026-09-15