幽门螺杆菌逃逸巨噬细胞免疫监视的进化策略

doi:10.3969/j.issn.1004-583X.2025.07.014

摘要/Abstract

摘要：

幽门螺杆菌通过多维度免疫逃逸策略长期定植于宿主胃黏膜,其与巨噬细胞的动态博弈是致病核心。该病原体通过分泌CagA、VacA等毒力因子干扰巨噬细胞功能,抑制自噬流(如靶向LC3-Ⅱ/Beclin-1复合体)并诱导M2型极化,构建免疫抑制微环境;同时激活Janus激酶/信号转导与转录激活因子、核因子κB等信号通路,重塑宿主基因表达谱(如差异基因富集于趋化因子及炎症相关通路),促进慢性炎症向胃癌转化。基因组多态性(如CagA变异)及适应性突变赋予其环境耐受与耐药性,加剧临床治疗难度。近年研究发现,幽门螺杆菌通过调控细胞程序性死亡-配体1表达、代谢重编程等新机制逃逸免疫监视,动物模型与临床数据证实其与胃癌发展的强相关性。未来研究需整合多组学技术(单细胞转录组、空间代谢组)解析宿主-菌群互作网络,并开发靶向毒力因子或免疫检查点的精准疗法。阐明幽门螺杆菌免疫逃逸的分子逻辑,将为阻断“炎-癌转化”及新型疫苗设计提供理论依据。

关键词: 幽门螺杆菌, 巨噬细胞, 免疫监视, 进化策略, 感染

中图分类号:

R377

陈剑, 周利, 张春婷, 黄奕然, 张毅. 幽门螺杆菌逃逸巨噬细胞免疫监视的进化策略[J]. 临床荟萃, 2025, 40(7): 663-668.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: http://www.lchc.cn/CN/10.3969/j.issn.1004-583X.2025.07.014

http://www.lchc.cn/CN/Y2025/V40/I7/663

图/表 5

参考文献 25

[1]	Fan J, Zhu J, Xu H.. Strategies of helicobacter pylori in evading host innate and adaptive immunity:Insights and prospects for therapeutic targeting[J]. Front Cell Infect Microbiol, 2024,14:1342913.
[2]	Niu Q, Zhu J, Yu X, et al. Immune response in H.pylori-associated gastritis and gastric cancer[J]. Gastroenterol Res Pract, 2020, 2020: 9342563.
[3]	Neuper T, Frauenlob T, Posselt G, et al. Beyond the gastric epithelium-the paradox of helicobacter pylori-induced immune responses[J]. Curr Opin Immunol, 2022,76:102208.
[4]	Chen D, Wu L, Liu X, et al. Helicobacter pylori CagA mediated mitophagy to attenuate the NLRP3 inflammasome activation and enhance the survival of infected cells[J]. Sci Rep, 2024, 14(1):21648. doi: 10.1038/s41598-024-72534-5 pmid: 39289452
[5]	Fei X, Chen S, Li L, et al. Helicobacter pylori infection promotes M1 macrophage polarization and gastric inflammation by activation of NLRP3 inflammasome via TNF/TNFR1 axis[J]. Cell Commun Signal, 2025, 23(1):6. doi: 10.1186/s12964-024-02017-7 pmid: 39762835
[6]	Li X, Pan K, Vieth M, et al. JAK-STAT1 signaling pathway is an early response to helicobacter pylori infection and contributes to immune escape and gastric carcinogenesis[J]. Int J Mol Sci, 2022, 23(8):4147.
[7]	de Visser KE, Eichten A, Coussens LM.. Paradoxical roles of the immune system during cancer development[J]. Nat Rev Cancer, 2006, 6(1):24-37. doi: 10.1038/nrc1782 pmid: 16397525
[8]	Wei YF, Xie SA, Zhang ST. Current research on the interaction between helicobacter pylori and macrophages[J]. Mol Biol Rep, 2024, 51(1):497.
[9]	郭晓灿. 巨噬细胞在肝脏肿瘤起始细胞存活和肝癌发生中的关键作用研究[D]. 杭州: 浙江大学, 2016:10-11.
[10]	Chonwerawong M, Ferrand J, Chaudhry HM, et al. Innate immune molecule NLRC5 protects mice from helicobacter-induced formation of gastric lymphoid tissue[J]. Gastroenterology, 2020, 159(1):169-182.e8. doi: S0016-5085(20)30329-2 pmid: 32169428
[11]	Shi Y, Yang Z, Zhang T, et al. SIRT1-targeted miR-543 autophagy inhibition and epithelial-mesenchymal transition promotion in helicobacter pylori CagA-associated gastric cancer[J]. Cell Death Dis, 2019, 10(9):625. doi: 10.1038/s41419-019-1859-8 pmid: 31423013
[12]	Wei YF, Li X, Zhao MR, et al. Helicobacter pylori disrupts gastric mucosal homeostasis by stimulating macrophages to secrete CCL3[J]. Cell Commun Signal, 2024, 22(1):263.
[13]	Wang X, Wang B, Gao W, et al. Helicobacter pylori inhibits autophagic flux and promotes its intracellular survival and colonization by down-regulating SIRT1[J]. J Cell Mol Med, 2021, 25(7):3348-3360.
[14]	Malfertheiner P, Camargo MC, El-omar E, et al. Helicobacter pylori infection[J]. Nat Rev Dis Primers, 2023, 9(1):19. doi: 10.1038/s41572-023-00431-8 pmid: 37081005
[15]	Chehelgerdi M, Heidarnia F, Dehkordi FB, et al. Immunoinformatic prediction of potential immunodominant epitopes from cagW in order to investigate protection against helicobacter pylori infection based on experimental consequences[J]. Funct Integr Genomics, 2023, 23(2):107.
[16]	何灿封. 基于PPARG探讨益肺散结丸干预巨噬细胞M2极化抑制肺癌免疫逃逸机制[D]. 广州: 广州中医药大学, 2024:1-2.
[17]	Whitmire JM, Merrell DS. Helicobacter pylori genetic polymorphisms in gastric disease development[J]. Adv Exp Med Biol, 2019,1149:173-194.
[18]	Hanafiah A, Lopes BS. Genetic diversity and virulence characteristics of helicobacter pylori isolates in different human ethnic groups[J]. Infect Genet Evol, 2020,78:104135.
[19]	顾晓, 邢莹莹. 幽门螺杆菌CagA诱导胃部炎癌转化的研究进展[J]. 中国药科大学学报, 2025, 56(1):132-138.
[20]	Kinoshita-daitoku R, Kiga K, Sanada T, et al. Mutational diversity in mutY deficient helicobacter pylori and its effect on adaptation to the gastric environment[J]. Biochem Biophys Res Commun, 2020, 525(3):806-811.
[21]	Zhang T, Tang X. Beyond metaplasia:Unraveling the complex pathogenesis of autoimmune atrophic gastritis and its implications for gastric cancer risk[J]. QJM, 2025,24:hcaf028.
[22]	蒋明远, 黄华, 路明亮, 等. 益生菌在根除幽门螺杆菌治疗中的应用及研究进展[J]. 国际消化病杂志, 2019, 39(2):124-127.
[23]	Olnes MJ, Martinson HA. Recent advances in immune therapies for gastric cancer[J]. Cancer Gene Ther, 2021, 28(9):924-934. doi: 10.1038/s41417-021-00310-y pmid: 33664460
[24]	Chen C, Wang J, Pan D, et al. Applications of multi-omics analysis in human diseases[J]. Med Comm(2020),2023, 4(4):e315.
[25]	Wang H, Lin K, Zhang Q, et al. HyperTMO:A trusted multi-omics integration framework based on hypergraph convolutional network for patient classification[J]. Bioinformatics, 2024, 40(4):btae159.

参考文献	机制类别	作用方式	关键分子/通路	免疫效应	临床关联
Niu等^[2]	表面分子调节	改变表面抗原表达,干扰巨噬细胞识别与吞噬功能	Lewis抗原、Toll样受体信号通路	抑制巨噬细胞抗菌活性,逃逸免疫监视	促进慢性感染及胃癌进展
Neupe等^[3]	巨噬细胞极化调节	诱导巨噬细胞向抗炎表型(M2)转化,抑制促炎因子分泌	白介素(interleukin,IL)-10、信号转导与转录激活因子(signal transducer and activator of tran-ions,STAT)3/过氧化物酶体增殖物激活受体γ通路	降低杀菌能力,增强免疫耐受	需联合免疫调节治疗提高根除率
Chen等^[4]	线粒体功能障碍	CagA蛋白诱导线粒体膜通透性改变,干扰能量代谢与炎症反应	CagA、细胞色素c、caspase	巨噬细胞清除能力下降,炎症反应失衡	靶向CagA可恢复巨噬细胞功能
Fei等^[5]	炎症小体激活	激活NLRP3炎症小体,促进IL-1β等炎症因子过度释放	NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor thermal protein domain associated protein 3, NLRP3)、IL-1β	炎症反应失控,导致胃黏膜损伤	抑制NLRP3可减轻组织损伤
Li等^[6]	免疫检查点调控	上调巨噬细胞或周围细胞PD-L1表达,抑制T细胞活性	细胞程序性死亡-配体1(programmed cell death ligand 1,PD-L1)/程序性死亡受体1(programmed death 1,PD-1)通路	抑制T细胞介导的免疫应答,促进免疫逃逸	免疫检查点抑制剂或可辅助治疗胃癌

参考文献	机制类别	作用方式	关键分子/通路	免疫效应	临床关联
Niu等^[2]	表面分子调节	改变表面抗原表达,干扰巨噬细胞识别与吞噬功能	Lewis抗原、Toll样受体信号通路	抑制巨噬细胞抗菌活性,逃逸免疫监视	促进慢性感染及胃癌进展
Neupe等^[3]	巨噬细胞极化调节	诱导巨噬细胞向抗炎表型(M2)转化,抑制促炎因子分泌	白介素(interleukin,IL)-10、信号转导与转录激活因子(signal transducer and activator of tran-ions,STAT)3/过氧化物酶体增殖物激活受体γ通路	降低杀菌能力,增强免疫耐受	需联合免疫调节治疗提高根除率
Chen等^[4]	线粒体功能障碍	CagA蛋白诱导线粒体膜通透性改变,干扰能量代谢与炎症反应	CagA、细胞色素c、caspase	巨噬细胞清除能力下降,炎症反应失衡	靶向CagA可恢复巨噬细胞功能
Fei等^[5]	炎症小体激活	激活NLRP3炎症小体,促进IL-1β等炎症因子过度释放	NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor thermal protein domain associated protein 3, NLRP3)、IL-1β	炎症反应失控,导致胃黏膜损伤	抑制NLRP3可减轻组织损伤
Li等^[6]	免疫检查点调控	上调巨噬细胞或周围细胞PD-L1表达,抑制T细胞活性	细胞程序性死亡-配体1(programmed cell death ligand 1,PD-L1)/程序性死亡受体1(programmed death 1,PD-1)通路	抑制T细胞介导的免疫应答,促进免疫逃逸	免疫检查点抑制剂或可辅助治疗胃癌

节点1	节点2	数据库标注	文献关联	综合评分
LRP5	FZD4	0.90	0.994	0.999
SERPINB3	SERPINB4	0.00	0.823	0.989
CXCL10	CXCL9	0.90	0.918	0.989
IL2RA	JAK3	0.90	0.897	0.989
IL1RN	IL1A	0.90	0.848	0.986
STAT1	JAK3	0.90	0.803	0.982
IL1A	CXCL10	0.90	0.802	0.981
IL7R	JAK3	0.80	0.795	0.977
NAMPT	NMNAT2	0.90	0.680	0.970
NMNAT2	QPRT	0.90	0.611	0.962
MMP3	MMP1	0.90	0.912	0.953
BAMBI	GREM1	0.90	0.557	0.953
STAT1	IFIT1	0.30	0.742	0.952
NAMPT	NNMT	0.90	0.527	0.950
IGF1	MMP1	0.90	0.483	0.946
STAT1	IL2RA	0.90	0.475	0.945
IRAK2	IL1A	0.90	0.402	0.940
VCAN	CSGALNACT1	0.90	0.379	0.936
MMP10	MMP1	0.90	0.764	0.936
BMP6	BAMBI	0.90	0.391	0.936
STAT1	CXCL12	0.90	0.391	0.936
DAO	SHMT1	0.90	0.298	0.933
MMP10	MMP3	0.65	0.825	0.933
CYP3A5	CYP3A7	0.80	0.870	0.926
FOSB	ARC	0.90	0.276	0.926
IRAK2	IL1RN	0.90	0.258	0.926

节点1	节点2	数据库标注	文献关联	综合评分
LRP5	FZD4	0.90	0.994	0.999
SERPINB3	SERPINB4	0.00	0.823	0.989
CXCL10	CXCL9	0.90	0.918	0.989
IL2RA	JAK3	0.90	0.897	0.989
IL1RN	IL1A	0.90	0.848	0.986
STAT1	JAK3	0.90	0.803	0.982
IL1A	CXCL10	0.90	0.802	0.981
IL7R	JAK3	0.80	0.795	0.977
NAMPT	NMNAT2	0.90	0.680	0.970
NMNAT2	QPRT	0.90	0.611	0.962
MMP3	MMP1	0.90	0.912	0.953
BAMBI	GREM1	0.90	0.557	0.953
STAT1	IFIT1	0.30	0.742	0.952
NAMPT	NNMT	0.90	0.527	0.950
IGF1	MMP1	0.90	0.483	0.946
STAT1	IL2RA	0.90	0.475	0.945
IRAK2	IL1A	0.90	0.402	0.940
VCAN	CSGALNACT1	0.90	0.379	0.936
MMP10	MMP1	0.90	0.764	0.936
BMP6	BAMBI	0.90	0.391	0.936
STAT1	CXCL12	0.90	0.391	0.936
DAO	SHMT1	0.90	0.298	0.933
MMP10	MMP3	0.65	0.825	0.933
CYP3A5	CYP3A7	0.80	0.870	0.926
FOSB	ARC	0.90	0.276	0.926
IRAK2	IL1RN	0.90	0.258	0.926