miR-99a-5p在结核分枝杆菌感染宿主巨噬细胞中的免疫调控作用

doi:10.19982/j.issn.1000-6621.20220532

中国防痨杂志 ›› 2023, Vol. 45 ›› Issue (5): 464-471.doi: 10.19982/j.issn.1000-6621.20220532

miR-99a-5p在结核分枝杆菌感染宿主巨噬细胞中的免疫调控作用

史雨婷¹, 董静¹, 贾红彦¹, 朱传智¹, 杨斌², 李自慧¹, 孙琦¹, 杜博平¹, 邢爱英¹, 张宗德¹, 潘丽萍¹()

¹ 首都医科大学附属北京胸科医院/北京市结核病胸部肿瘤研究所耐药结核病研究北京市重点实验室, 北京 101149
² 首都医科大学附属北京胸科医院/北京市结核病胸部肿瘤研究所肿瘤研究中心, 北京 101149

收稿日期:2023-01-15 出版日期:2023-05-10 发布日期:2023-04-25
通信作者: 潘丽萍 E-mail:panliping2006@163.com
基金资助:
国家自然科学基金(81902024);国家自然科学基金(82172279);国家自然科学基金(82070012);北京市自然科学基金(7192038);北京市自然科学基金(7212012);通州区运河计划人才项目(YH201807);通州区运河计划人才项目(YH202001);北京市医院管理中心青年职工创新工作室-创新梦工场(202136)

The role of miR-99a-5p in the immune regulation of host macrophages infected by Mycobacterium tuberculosis

Shi Yuting¹, Dong Jing¹, Jia Hongyan¹, Zhu Chuanzhi¹, Yang Bin², Li Zihui¹, Sun Qi¹, Du Boping¹, Xing Aiying¹, Zhang Zongde¹, Pan Liping¹()

¹ Beijing Key Laboratory for Drug Resistant Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute,Beijing Chest Hospital, Capital Medical University, Beijing 101149,China
² Cancer Research Center, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149,China

Received:2023-01-15 Online:2023-05-10 Published:2023-04-25
Contact: Pan Liping E-mail:panliping2006@163.com
Supported by:
National Natural Science Foundation(81902024);National Natural Science Foundation(82172279);National Natural Science Foundation(82070012);Beijing Natural Science Foundation(7192038);Beijing Natural Science Foundation(7212012);Tongzhou Yunhe Project(YH201807);Tongzhou Yunhe Project(YH202001);Beijing Hospital Management Center Young Workers Innovation Studio-Innovation Dreamworks(202136)

摘要/Abstract

摘要： 目的初步探讨结核分枝杆菌(Mycobacterium tuberculosis, MTB)感染THP-1细胞内特异miRNA在宿主抗结核免疫中的作用。方法提取MTB感染及未感染THP-1细胞RNA,基于Illumina NovaSeq6000二代测序平台检测THP-1细胞内miRNA表达谱。采集4名健康受试者6ml外周血并分离人原代巨噬细胞。应用实时荧光PCR(qRT-PCR)技术验证MTB感染THP-1细胞内特异miRNA并检测人原代巨噬细胞中靶标miRNA的表达水平。构建miRNA过表达载体,经慢病毒转染THP-1巨噬细胞获得稳定的过表达细胞株,使用qRT-PCR检测H37Rv感染的miRNA过表达细胞及对照空载体细胞中的肿瘤坏死因子α(TNF-α)及γ-干扰素(IFN-γ)表达水平。结果从16个二代测序结果表达差异明显的miRNA分子中选取既往未作研究且差异最为明显的miR-99a-5p(P=0.021)作为研究靶基因。通过qRT-PCR在THP-1细胞及原代巨噬细胞中验证,发现miR-99a-5p在THP-1感染组和原代巨噬细胞内的表达量(分别为0.482±0.148和0.433±0.072)均明显低于未感染组(1.536±0.290和1.113±0.218),差异均有统计学意义(t=6.476,P<0.001;t=3.167, P=0.019)。MTB感染miR-99a-5p过表达细胞后24h的菌落形成单位(CFU)[64.0×10⁴(52.0×10⁴,87.0×10⁴)]明显高于MTB感染的对照空载体细胞内CFU[17.0×10⁴(16.0×10⁴,24.0×10⁴)],差异有统计学意义(Z=-2.323, P=0.029)。与MTB感染的对照空载体细胞相比,MTB感染的miR-99a-5p过表达细胞内TNF-α及IFN-γ的mRNA相对表达水平分别由1.018±0.310和1.687±0.135下降至0.740±0.001和0.631±0.374,差异均有统计学意义(t=4.631, P=0.010;t=3.349, P=0.010)。结论 miR-99a-5p可抑制TNF-α及IFN-γ的释放,促进MTB在巨噬细胞内的生长。MTB感染后宿主miR-99a-5p的下调表达可能在宿主抗结核感染免疫中发挥重要作用。

关键词: 分枝杆菌,结核, 芯片分析技术, 微RNAs, 巨噬细胞, 免疫调节

Abstract:

Objective: To explore the role of specific microRNA in THP-1 cells mediated host defense against Mycobacterium tuberculosis (MTB) infection. Methods: Total RNA were extracted from THP-1 cells with or without MTB (H37Rv) infection, and then the miRNA expression profiles in THP-1 cells with or without MTB infection were identified using Illumina NovaSeq6000 next-generation sequencing platform. Four health controls were recruited and the human monocyte-derived macrophage (hMDM) were separated. Validation of differentially expressed miRNA between MTB infected and uninfected THP-1 cells, as well as that between MTB infected and uninfected hMDM, were performed by quantitative real-time PCR (qRT-PCR). The miRNA overexpression vector was constructed and transfected into THP-1 macrophages by lentivirus. The expression level of tumor necrosis factor-α(TNF-α), interferon-γ(IFN-γ) and colony-forming unit (CFU) in H37Rv infected THP-1 cells which were transfected with miRNA overexpression vector or control empty vector was tested using qRT-PCR. Results: miR-99a-5p was selected as the study target gene (P=0.021) by not previously studied and most significantly different, from 16 miRNA molecules with significant expression differences in second-generation sequencing results. By qRT-PCR validation in THP-1 cells and primary macrophages, miR-99a-5p expression within THP-1 infected groups (0.482±0.148) and primary macrophages (0.433±0.072) were significantly lower than the uninfected group (1.536±0.290 and 1.113±0.218)(t=6.476,P<0.001; t=3.167,P=0.019). CFU results of the THP-1 cells infected by MTB showed that the intracellular bacteria amount of miR-99a-5p overexpression cells at 24 h after infection was 64.0×10⁴ (52.0×10⁴,87.0×10⁴), which was significantly higher than that in the control cells (17.0×10⁴ (16.0×10⁴,24.0×10⁴))(Z=-2.323, P=0.029). Furthermore, the expression levels of TNF-α and IFN-γ in MTB infected miR-99a-5p over expression cells were 1.018±0.310 and 1.687±0.135, which were significantly lower than TNF-α (0.740±0.001) and IFN-γ (0.631±0.374) those in the MTB infected control cells (t=4.631, P=0.010; t=3.349, P=0.010). Conclusion: miR-99a-5p can inhibit the release of TNF-α and IFN-γ, promote the growth of MTB in macrophages. Therefore, the decreased miR-99a-5p expression after MTB infection may play a protective role in host innate immunity against MTB infection.

Key words: Mycobacterium tuberculosis, Microarray technology, MicroRNAs, Macrophages, Immunomodulation

中图分类号:

史雨婷, 董静, 贾红彦, 朱传智, 杨斌, 李自慧, 孙琦, 杜博平, 邢爱英, 张宗德, 潘丽萍. miR-99a-5p在结核分枝杆菌感染宿主巨噬细胞中的免疫调控作用[J]. 中国防痨杂志, 2023, 45(5): 464-471. doi: 10.19982/j.issn.1000-6621.20220532

Shi Yuting, Dong Jing, Jia Hongyan, Zhu Chuanzhi, Yang Bin, Li Zihui, Sun Qi, Du Boping, Xing Aiying, Zhang Zongde, Pan Liping. The role of miR-99a-5p in the immune regulation of host macrophages infected by Mycobacterium tuberculosis[J]. Chinese Journal of Antituberculosis, 2023, 45(5): 464-471. doi: 10.19982/j.issn.1000-6621.20220532

图/表 4

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参考文献 37

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样本名称	测序类型	碱基序列长度(bp)	碱基质量 (%)	结果
THP-1-1640-1	miRNA seq	21 289 140	98.73	Pass
THP-1-1640-2	miRNA seq	26 075 024	98.66	Pass
THP-1-1640-3	miRNA seq	21 649 327	98.71	Pass
THP-1-Rv-1	miRNA seq	26 065 198	98.59	Pass
THP-1-Rv-2	miRNA seq	24 885 359	98.65	Pass
THP-1-1-Rv-3	miRNA seq	22 724 008	98.73	Pass

miRNA名称	Log2FC	P值	miRNA名称	Log2FC	P值
has-miR-216a-5p	4.861	<0.001	has-miR-217	1.843	0.031
has-miR-31-5p	2.998	0.000	has-miR-301b-5p	3.082	0.045
has-miR-409-3p	Inf	<0.001	has-miR-3190-3p	Inf	0.031
has-miR-125b-5p	1.017	0.007	has-miR-33a-5p	1.210	0.047
has-miR-127-3p	2.795	0.006	has-miR-411-5p	2.275	0.045
has-miR-1307-5p	2.335	0.012	has-miR-4518	Inf	0.032
has-miR-15a-3p	1.889	0.048	has-miR-4755-5p	Inf	0.026
has-miR-190a-3p	2.590	0.025	has-miR-99a-5p	2.191	0.021

组别	感染4h菌落形成单位计数(×10⁴)	感染24h菌落形成单位计数(×10⁴)
对照空载体组	50.0(26.0,84.0)	17.0(16.0,24.0)
miR-99a-5p过表达组	51.0(37.0,56.0)	64.0(52.0,87.0)
Z值	-0.145	-2.323
P值	0.886	0.029

组别	TNF-α相对表达量		IFN-γ相对表达量
组别	未感染组	感染组(6h)	未感染组	感染组(6h)
对照空载体组	0.499±0.005	1.018±0.310	0.530(0.476,2.082)	1.687±0.135
miR-99a-5p过表达组	0.516±0.016	0.740±0.001	0.522(0.513,1.058)	0.631±0.374
t值	-0.169	4.631	1.135	3.349
P值	0.874	0.010	0.100	0.010

miR-99a-5p在结核分枝杆菌感染宿主巨噬细胞中的免疫调控作用

The role of miR-99a-5p in the immune regulation of host macrophages infected by Mycobacterium tuberculosis

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