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中华实验和临床感染病杂志(电子版)

中华实验和临床感染病杂志(电子版) ›› 2024, Vol. 18 ›› Issue (03) : 135 -141. doi: 10.3877/cma.j.issn.1674-1358.2024.03.002

论著

干扰素诱导蛋白16-干扰素基因刺激因子通路在柯萨奇病毒A6型感染手足口病患儿的表达及其临床意义
李亚萍1, 张萌1, 李博驹1, 刘晨瑞1, 苟国娥1, 李嘉昕2, 张玉凤2, 席淼2, 邓慧玲3,†()   
  1. 1. 710004　西安市，西安交通大学第二附属医院感染科
    2. 710002　西安市，西安市儿童医院感染科
    3. 710003　西安市，西安市中心医院儿科
  • 收稿日期:2024-03-16 出版日期:2024-06-15
  • 通信作者: 邓慧玲
  • 基金资助:
    国家自然科学基金青年项目(No. 81701632); 陕西省自然科学基础研究计划资助项目(No. 2022JQ-916); 陕西省重点产业创新链（群）-社会发展领域(No. 2022ZDLSF01-05); 西安市创新能力强基计划-医学研究项目(No. 21YXYJ006)

Expression and clinical significance of interferon gamma inducible protein 16-stimulator of interferon genes pathway in children with hand, foot and mouth disease infected by Coxsackie virus A6

Yaping Li1, Meng Zhang1, Boju Li1, Chenrui Liu1, Guoe Gou1, Jiaxin Li2, Yufeng Zhang2, Miao Xi2, Huiling Deng3,†()   

  1. 1. Department of Infectious Diseases, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
    2. Department of Infectious Diseases, Xi’an Children’s Hospital, Xi’an 710002, China
    3. Department of Pediatrics, Xi’an Central Hospital, Xi’an 710003, China
  • Received:2024-03-16 Published:2024-06-15
  • Corresponding author: Huiling Deng
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引用本文：

李亚萍, 张萌, 李博驹, 刘晨瑞, 苟国娥, 李嘉昕, 张玉凤, 席淼, 邓慧玲. 干扰素诱导蛋白16-干扰素基因刺激因子通路在柯萨奇病毒A6型感染手足口病患儿的表达及其临床意义[J]. 中华实验和临床感染病杂志(电子版), 2024, 18(03): 135-141.

Yaping Li, Meng Zhang, Boju Li, Chenrui Liu, Guoe Gou, Jiaxin Li, Yufeng Zhang, Miao Xi, Huiling Deng. Expression and clinical significance of interferon gamma inducible protein 16-stimulator of interferon genes pathway in children with hand, foot and mouth disease infected by Coxsackie virus A6[J]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2024, 18(03): 135-141.

目的

探索干扰素诱导蛋白16（IFI16）和干扰素基因刺激因子（STING）在柯萨奇病毒A6型（CV-A6）感染手足口病（HFMD）患儿的表达及其临床意义。

方法

收集2023年5月至8月西安交通大学第二附属医院、西安市儿童医院和西安市中心医院收治的CV-A6感染HFMD患儿外周血标本55例，同时匹配收集同期健康体检儿童血清20例作为对照。入组HMFD患儿根据疾病轻重程度分为轻症、重症患儿。采用酶联免疫吸附法（ELISA）检测不同严重程度、急性期与恢复期患儿IFI16、环化GMP-AMP合酶（cGAS）、STING、干扰素调节因子3（IRF-3）和α干扰素（IFN-α）的表达水平。

结果

与对照组相比，轻症CV-A6 HFMD患儿IFI16和STING的表达均升高，而在重症CV-A6 HFMD患儿中则表达下降[15.92（13.34，19.13）ng/ml vs.13.66（11.91，14.83）ng/ml：Z =－2.200、P = 0.028；1 345.45（991.55，1843.63）pg/ml vs. 1 072.26（947.25，1 180.97）pg/ml：Z =－2.000、P = 0.046]，仅STING在重症CV-A6型HFMD患儿急性期与恢复期间表达差异具有统计学意义[1 072.26（947.25，1 180.97） vs. 1 665.29（1 341.62，1 961.83）：Z =－3.237、P = 0.001]；与对照组相比，IFN-α在轻症CV-A6 HFMD患儿表达降低[864.47（721.41，952.89）pg/ml vs. 715.08（575.41，896.69）pg/ml，Z =－2.054、P = 0.040]；但cGAS、IRF3在对照组、轻症和重症HFMD患儿间表达差异均无统计学意义（P均> 0.05）。Sperman相关性分析显示，IFI16和STING表达具有正相关性（r = 0.286、P = 0.013）。临床特征方面，神经受累（病理反射阳性）患儿IFI16（Z =－3.307、P = 0.001）和STING（Z =－2.702、P = 0.007）水平均低于病理反射阴性患儿，有肢体抽动（Z =－2.489、P = 0.013）、精神差（Z =－2.542、P = 0.011）和高血糖水平（Z =－2.828、P = 0.005）患儿的IFI16水平也低于无以上特征的患儿，IFI16与血糖水平也具有负相关性（Sperman相关性分析：r =－0.427、P = 0.001）。

结论

CV-A6感染可激活IFI16-STING通路。IFI16和STING的表达与CV-A6型HFMD的重症化相关联，其较高的表达水平可能是机体抵御重症化的保护因素。

关键词: 手足口病, 脱氧核糖核酸感受器, 干扰素诱导蛋白16, 干扰素基因刺激因子
Objective

To investigate the expression and clinical significance of interferon gamma inducible protein 16 (IFI16) and stimulator of interferon genes (STING) of children with hand, foot and mouth disease (HFMD) infected by Coxsackie virus A6 (CV-A6).

Methods

The peripheral blood samples of 55 children with CV-A6 HFMD admitted to the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Children’s Hospital and Xi’an Central Hospital from May to August 2023 were collected, and 20 samples were collected from healthy children as controls. According to the severity of the disease, the children were divided into mild and severe cases. Enzyme-linked immunosorbent (ELISA) assay was used to detect the expression levels of IFI16, Cyclic GMP-AMP Synthase (cGAS), STING, interferon regulatory factor 3 (IRF-3) and interferon-α (IFN-α) in different severity, acute phase and recovery phase.

Results

Compared with control group, the expression of IFI16 and STING increased in mild CV-A6 HFMD children, and decreased in severe CV-A6 HFMD children [15.92 (13.34, 19.13) ng/ml vs. 13.66 (11.91, 14.83) ng/ml: Z =-2.200, P = 0.028; 1 345.45 (991.55, 1 843.63) pg/ml vs. 1 072.26 (947.25, 1 180.97) pg/ml: Z =-2.000, P = 0.046]. Only the expression of STING in children with severe CV-A6 HFMD was significantly different between the acute stage and the recovery stage [1 072.26 (947.25, 1 180.97) vs. 1 665.29 (1 341.62, 1 961.83): Z =-3.237, P = 0.001]. Compared with the control group, the expression of IFN-α in the mild CV-A6 HFMD group decreased [864.47 (721.41, 952.89) pg/ml vs. 715.08 (575.41, 896.69) pg/ml: Z =-2.054, P = 0.040]. There was no significant difference in the expression of cGAS and IRF3 among the control group, mild HFMD group and severe HFMD group (all P > 0.05). Sperman correlation analysis showed that IFI16 expression was positively correlated with STING expression (r = 0.286, P = 0.013). The expression of IFI16 (Z =-3.307, P = 0.001) and STING (Z =-2.702, P = 0.007) in children with nerve involvement (positive pathological reflex) were lower than those in children with negative pathological reflex. Children with limb twitching (Z =-2.489, P = 0.013), poor mental state (Z =-2.542, P = 0.011), and high blood glucose level (Z =-2.828, P = 0.005) also had lower IFI16 levels than those without such characteristics, and IFI16 was negatively correlated with blood glucose levels (Sperman correlation analysis: r =-0.427, P = 0.001).

Conclusions

CV-A6 infection can activate the IFI16-STING pathway. The expression of IFI16 and STING are associated with the severity of CV-A6-induced HFMD, and their higher expression levels may be a protective factor of the body against the progression to severe disease.

Key words: Hand, foot and mouth disease, Deoxyribonucleic acid receptor, Interferon inducible protein 16, Stimulator of interferon genes
表1 IFI16、cGAS、STING、IRF-3和IFN-α在各组研究对象中的表达[M（P25，P75）]
组别 例数 IFI16（ng/ml） cGAS（U/L） STING（pg/ml） IRF-3（pg/ml） IFN-α（pg/ml）
对照组 20 15.92（13.34，19.13） 562.34（353.25，609.44） 1345.45（991.55，1843.63） 103.28（84.22，136.87） 864.47（721.41，952.89）
轻症组 40 17.04（13.67，19.87） 553.29（381.92，652.61） 1441.03（1 083.92，1 792.79） 117.39（100.84，139.73） 715.08（575.41，896.69）
重症组 15 13.66（11.91，14.83） 572.07（500.70，694.95） 1 072.26（947.25，1 180.97） 132.46（92.92，150.20） 718.21（616.62，908.07）
K值   8.918 1.950 8.501 1.937 4.671
P值   0.012 0.377 0.014 0.380 0.097
Z1值   －0.776 －0.894 －0.674 －1.019 －2.054
P1值   0.438 0.371 0.500 0.308 0.040
Z2值   －2.200 －1.217 －2.000 －1.333 －1.467
P2值   0.028 0.224 0.046 0.191 0.142
Z3值   －2.891 －0.926 －2.910 －0.595 －0.643
P3值   0.004 0.354 0.004 0.552 0.521
图1 IFI16、cGAS、STING和IFN-α在HFMD患儿急性期与恢复期的表达注：A～D：轻症CV-A6型HFMD；E～H：重症CV-A6型HFMD
图2 患儿IFI16与STING和血糖水平的相关性注：A：IFI16和STING相关性；B：IFI16和血糖水平相关性
表2 不同临床特征HFMD患儿IFI16和STING的表达[M（P25，P75）]
临床特征 例数 IFI16（ng/ml） Z值 P值 STING（pg/ml） Z值 P值
病理反射     －3.307 0.001   －2.702 0.007
阴性 40 17.04（13.72，19.87）     1 441.03（1 074.60，1 792.79）    
阳性 15 13.14（11.91，14.08） 1 122.88（947.25，1 243.11）
肢体抽动     －2.489 0.013   －0.673 0.501
无 50 15.72（13.63，19.44）     1 313.31（1 063.10，1 709.28）    
有 5 12.14（11.50，14.12） 1 072.26（984.99，1 601.14）
精神差     －2.542 0.011   －0.802 0.423
无 32 17.13（13.71，19.87）     1 349.11（1 054.32，1 775.21）    
有 23 14.07（12.14，16.48） 1 180.97（1009.39，1 614.36）
血糖a     －2.828 0.005   －1.330 0.184
< 3.81 mmol/L 28 17.60（14.14，20.98）     1 441.03（1 043.16，1 779.79）    
≥ 3.81 mmol/L 27 13.69（12.64，17.16） 1 149.90（1 049.93，1 414.69）
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