自噬在细菌感染中的作用机制研究进展

doi:10.16431/j.cnki.1671-7236.2025.09.045

摘要/Abstract

摘要： 细菌感染是指致病菌或条件致病菌侵入血液循环中生长繁殖，产生毒素和其他代谢产物所引起的急性全身性感染。它通过破坏或利用自噬毒力蛋白或相关分子逃避自噬，影响多种器官和组织，对畜禽的健康和生产性能造成了严重的影响。细菌具有血清型多样、耐药性高且在自然界中的存活时间长等特点，这使得其防治工作变得尤为复杂。细菌感染涉及多个通路，多数研究主要集中在细菌代谢、核酸合成、毒素及毒力因子、免疫调控、炎症与免疫病理机制等方面，同时自噬与各机制密切相关，因此细菌感染与自噬的研究逐渐成为当前微生物学、免疫学和细胞生物学交叉领域的热点之一。自噬在宿主防御细菌感染中扮演重要角色，但细菌也可能通过干扰自噬通路逃逸宿主免疫清除。因此，深入解析细菌与自噬相互作用的分子机制，探寻新的自噬调控靶点，对于开发新型抗菌药物和治疗方案具体重要意义。笔者总结了自噬在细菌感染中的作用，就宿主细胞如何通过自噬机制逃避机体细菌感染展开论述，以期为靶向自噬治疗细菌感染提供新的思路。

关键词: 细菌感染; 自噬; 自噬体; 信号通路

Abstract: Bacterial infection refers to an acute systemic infection caused by pathogenic bacteria or conditional pathogenic bacteria that invade the blood circulation to grow and multiply and produce toxins and other metabolites.It evades autophagy by destroying or utilizing autophagic virulence proteins or related molecules,affecting various organs and tissues,and causing serious impacts on the health and production performance of livestock and poultry.Due to the characteristics of diverse serotypes,high drug resistance and long survival time in nature,which makes the prevention and control of bacteria particularly complex. At the same time,bacterial infection involves multiple pathways,and most of the research mainly focuses on bacterial metabolism,nucleic acid synthesis,toxins and virulence factors,immune regulation,inflammation and immunopathological mechanisms,etc.Meanwhile,autophagy is closely related to the mechanism.Therefore,the research on bacterial infection and autophagy had gradually become one of the hot spots in the intersection of microbiology,immunology and cell biology at present.Autophagy plays an important role in the host’s defense against bacterial infections,but bacteria may also evade the host’s immune clearance by interfering with the autophagy pathway.Therefore,an in-depth analysis of the molecular mechanism of the interaction between bacteria and autophagy and the exploration of new autophagy regulatory targets are of specific significance for the development of novel antibacterial drugs and treatment regimens.The author summarized the role of autophagy in bacterial infections and discussed how host cells evade bacterial infections in the body through the autophagy mechanism,so as to provide new ideas for targeted autophagy treatment of bacterial infection.

Key words: bacterial infection; autophagy; autophagosome; signal pathway

中图分类号:

S852.21

雷兴芬, 李舜, 黄云飞, 李亚娟, 孙芹芹, 付强. 自噬在细菌感染中的作用机制研究进展[J]. 中国畜牧兽医, 2025, 52(9): 4505-4514.

LEI Xingfen, LI Shun, HUANG Yunfei, LI Yajuan, SUN Qinqin, FU Qiang. Research Progress on the Mechanism of Autophagy in Bacterial Infection[J]. China Animal Husbandry & Veterinary Medicine, 2025, 52(9): 4505-4514.

参考文献

[1] 孙舒慧.自噬相关蛋白在狼疮性肾炎肾组织中的表达及其临床意义研究[D].上海：上海交通大学,2016. SUN S H.Autophagy related proteins expression and their associations with clinicopathologic features of lupus nephritis[D].Shanghai:Shanghai Jiao Tong University,2016.(in Chinese)
[2] 黄超群,刘有华,王新霞.脂质自噬对肝脏脂质代谢的影响及机制研究进展[J].生命科学,2023,35(9):1147-1159. HUANG C Q,LIU Y H,WANG X X.Role and mechanisms of lipophagy on liver lipid metabolism[J]. Chinese Bulletin of Life Sciences,2023,35(9):1147-1159.(in Chinese)
[3] 刘继宇,何红云,邓仪昊.缺血性脑卒中后神经元自噬流障碍的病理机制研究进展[J].生理学报,2024,76(1):97-104. LIU J Y,HE H Y,DENG Y H.Pathogenic mechanisms of impaired neuronal autophagy flux after ischemic stroke[J].Acta Physiologica Sinica,2024,76(1):97-104.(in Chinese)
[4] 郁悦,程文秀,刁翰林,等.从中医阴阳理论探讨细胞自噬与子宫内膜异位性疾病的相关性[J].中华中医药学刊,2020，38(6):42-45. YU Y,CHENG W X,DIAO H L,et al.Study on relationship between autophagy and endometriosis from Yin-Yang theory of traditional Chinese medicine [J]. Chinese Archives of Traditional Chinese Medicine，2020，38(6):42-45.(in Chinese)
[5] DING X,JIANG X,TIAN R,et al.RAB2 regulates the formation of autophagosome and autolysosome in mammalian cells[J].Autophagy,2019,15(10):1774-1786.
[6] 吕兴娇.HDAC6调控组蛋白H3乙酰化和自噬在丁酸钠减轻小鼠肠缺血再灌注损伤中的作用[D].兰州：兰州大学,2023. LYU X J.Role of HDAC6 regulates histone H3 acetylation and autophagy in sodium butyrate attenuating intestinal ischemia-reperfusion injury in mice[D].Lanzhou:Lanzhou University,2023.(in Chinese)
[7] 王樱楠.蛇床子素通过调控PI3K/Akt/mTOR信号通路减轻LPS诱导的小鼠乳腺炎[D].合肥：安徽农业大学,2023. WANG Y N.Osthol alleviates LPS-induced mastitis in mice by regulating the PI3K/Akt/mTOR signaling pathway[D].Hefei:Anhui Agricultural University,2023.(in Chinese)
[8] FILALI-MOUNCEF Y,HUNTER C,ROCCIO F,et al.The menage a trois of autophagy,lipid droplets and liver disease[J].Autophagy,2022,18(1):50-72.
[9] 孙永楚.c-Jun通过PI3K/Akt-mTOR信号通路介导鼻咽癌细胞自噬发生与放射敏感性的研究[D].南宁：广西医科大学,2019. SUN Y C.c-Jun mediated autophagy and radiosensitivity of nasopharyngeal carcinoma cells via PI3K/Akt-mTOR signaling pathway[D].Nanning:Guangxi Medical University,2019.(in Chinese)
[10] 曾思雨,杜磊,邢怡桥.自噬在视网膜和眼部疾病中的研究进展[J].国际眼科杂志,2023,23(10):1662-1666. ZENG S Y,DU L,XING Y Q.Research progress of autophagy in retinal and eye diseases[J].International Eye Science,2023,23(10):1662-1666.(in Chinese)
[11] ZACHARI M,GANLEY I G.The mammalian ULK1 complex and autophagy initiation[J]. Essays in Biochemistry，2017，61(6):585-596.
[12] AMAN Y,SCHMAUCK-MEDINA T,HANSEN M,et al.Autophagy in healthy aging and disease[J].Nature Aging,2021,1(8):634-650.
[13] XU Y,WAN W.Acetylation in the regulation of autophagy[J].Autophagy,2023,19(2):379-387.
[14] LI X,YANG K B,CHEN W,et al.CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (Beclin-1) inhibit autophagy and promote tumor progression[J].Autophagy,2021,17(12):4323-4340.
[15] 乔秋江.FOXM1通过自噬途径对胶质瘤生长及耐药性的影响及机制研究[D].济南：山东大学,2022. QIAO Q J.The effect and mechanism of FOXM1 on progression and chemoresistance of gliomas via regulating autophagy[D].Jinan:Shandong University,2022.(in Chinese)
[16] FENG X,ZHANG H,MENG L,et al.Hypoxia-induced acetylation of PAK1 enhances autophagy and promotes brain tumorigenesis via phosphorylating ATG5 [J].Autophagy,2021,17(3):723-742.
[17] 武春艳,杨意,杨霞,等.自噬小体的生物发生和成熟[J].中国细胞生物学学报,2024,46(1):118-128. WU C Y,YANG Y,YANG X,et al.Autophagosome biogenesis and maturation [J].Chinese Journal of Cell Biology,2024,46(1):118-128.(in Chinese).
[18] GAO Y,ZHENG X,CHANG B,et al.Intercellular transfer of activated STING triggered by RAB22A-mediated non-canonical autophagy promotes antitumor immunity[J].Cell Research,2022,32(12):1086-1104.
[19] KAUR J,DEBNATH J.Autophagy at the crossroads of catabolism and anabolism[J].Nature Reviews Molecular Cell Biology,2015,16(8):461-472.
[20] 屈雅萍.氧固醇结合蛋白OSBPL3对胃癌细胞自噬和增殖的影响机制研究[D].镇江：江苏大学,2021. QU Y P.OSBPL3 regulate the autophagy and proliferation of gastric cancer cells[D].Zhenjiang:Jiangsu Jiangsu University,2021.(in Chinese)
[21] 牟俊洁.光周期对黑线仓鼠睾丸结构与功能的调控[D].曲阜：曲阜师范大学,2021. MOU J J.Regulation of photoperiod on the structure and function of striped dwarf hamster[D].Qufu:Qufu Normal University,2021.(in Chinese)
[22] ZHANG X,WANG Y,ZHU H,et al.Functional and transcriptome analysis of Streptococcus pyogenes virulence on loss of its secreted esterase[J].International Journal of Molecular Sciences,2022,23(14):7954.
[23] MURROW L,DEBNATH J.ATG12-ATG3 connects basal autophagy and late endosome function[J].Autophagy,2015,11(6):961-962.
[24] ZHANG S,LIU X,MOHAMMED S A A,et al.Adaptor SH3BGRL drives autophagy-mediated chemoresistance through promoting PIK3C3 translation and ATG12 stability in breast cancers[J].Autophagy,2022,18(8):1822-1840.
[25] AGROTIS A,PENGO N,BURDEN J J,et al.Redundancy of human ATG4 protease isoforms in autophagy and LC3/GABARAP processing revealed in cells[J].Autophagy,2019,15(6):976-997.
[26] CLARKE J,BALTAZAR M,ALSAHAG M,et al.Streptolysin O concentration and activity is central to in vivo phenotype and disease outcome in group A Streptococcus infection[J].Scientific Reports,2021,11(1):19011.
[27] NOZAWA T,IIBUSHI J,TOH H,et al.Intracellular group A Streptococcus induces golgi fragmentation to impair host defenses through streptolysin O and NAD-glycohydrolase[J].mBio，2021，12(1):e01974-20.
[28] BASTIAT-SEMPE B,LOVE J F,LOMAYESVA N,et al.Streptolysin O and NAD-glycohydrolase prevent phagolysosome acidification and promote group A Streptococcus survival in macrophages[J].mBio，2014，5(5):e01690-14.
[29] PAN F,ZHU M,LIANG Y,et al.Membrane vesicle delivery of a streptococcal M protein disrupts the blood-brain barrier by inducing autophagic endothelial cell death[J].Proceedings of the National Academy of Sciences of the United States of America,2023,120(24):e2219435120.
[30] NEUMANN Y,BRUNS S A,ROHDE M,et al.Intracellular Staphylococcus aureus eludes selective autophagy by activating a host cell kinase[J].Autophagy,2016,12(11):2069-2084.
[31] BELEN MESTRE M,ISABEL COLOMBO M.Staphylococcus aureus promotes autophagy by decreasing intracellular cAMP levels[J].Autophagy,2012,8(12):1865-1867.
[32] FANG L,WU H M,DING P S,et al.TLR2 mediates phagocytosis and autophagy through JNK signaling pathway in Staphylococcus aureus-stimulated RAW264.7 cells[J].Cell Signal，2014，26(4):806-814.
[33] WANG H,ZHOU Y,ZHU Q,et al.Staphylococcus aureus induces autohagy in bovine mammary epithelial cells and the formation of autophagosomes facilitates intracellular replication of Staph.aureus[J].Journal of Dairy Science,2019,102(9):8264-8272.
[34] MITCHELL G,GE L,HUANG Q,et al.Avoidance of autophagy mediated by PlcA or ActA is required for Listeria monocytogenes growth in macrophages[J].Nature Immunology，2015，83(5):2175-2184.
[35] VDOVIKOVA S,LUHR M,SZALAI P,et al.A novel role of Lilsteria monocytogenes membrane vesicles in inhibition of autophagy and cell death[J].Frontiers in Cellular and Infection Microbiology，2017，7:154.
[36] ZHANG Y,YAO Y,QIU X,et al.Listeria hijacks host mitophagy through a novel mitophagy receptor to evade killing[J].Nature Immunology，2019，20(4):433-446.
[37] MENG K,YANG J,XUE J,et al.A host E3 ubiquitin ligase regulates Salmonella virulence by targeting an SPI-2 effector involved in SIF biogenesis[J].mLife，2023，2(2):141-158.
[38] SUN D,GOU H,ZHANG Y,et al.Salmonella Typhimurium persistently infects host via its effector SseJ-induced PHB2-mediated mitophagy[J].Autophagy，2025，14:1-17.
[39] LUIS L B,ANA G T,CARLOS G E,et al.Salmonella promotes its own survival in B cells by inhibiting autophagy[J].Cells,2022,11(13):2061.
[40] XU Y,ZHOU P,CHENG S,et al.A bacterial effector reveals the V-ATPase-ATG16L1 axis that initiates xenophagy[J].Cell,2019,178(3):552.
[41] ETNA M P,SINIGAGLIA A,GRASSI A,et al. Mycobacterium tuberculosis induced miR-155 subverts autophagy by targeting ATG3 in human dendritic cells[J].PLoS Pathogens,2018,14(1):e1006790.
[42] CHAI Q,ZHANG Y,LIU C H.Mycobacterium tuberculosis:An adaptable pathogen associated with multiple human diseases[J].Frontiers in Cellular and Infection Microbiology,2018，8:158.
[43] DUAN L,YI M,CHEN J,et al. Mycobacterium tuberculosis EIS gene inhibits macrophage autophagy through up-regulation of IL-10 by increasing the acetylation of histone H3[J]. Biochemical and Biophysical Research Communications,2016,473(4):1229-1234.
[44] GE P,LEI Z,YU Y,et al.M.tuberculosis PknG manipulates host autophagy flux to promote pathogen intracellular survival[J].Autophagy,2022,18(3):576-594.
[45] DAI Y,ZHU C,XIAO W,et al.Mycobacterium tuberculosis hijacks host TRIM21-and NCOA4-dependent ferritinophagy to enhance intracellular growth[J].Journal of Clinical Investigation,2023，133(8):e159941.
[46] CAMPBELL-VALOIS F X,SACHSE M,SANSONETTI P J,et al.Escape of actively secreting Shigella flexneri from ATG8/LC3-positive vacuoles formed during cell-to-cell spread is facilitated by IcsB and VirA[J].mBio，2015，6(3):e02567-14.
[47] LOPEZ-MONTERO N,ENNINGA J.Diverted recycling-Shigella subversion of Rabs[J].Small GTPases,2018,9(5):365-374.
[48] YANG A,PANTOOM S,WU Y W.Elucidation of the anti-autophagy mechanism of the Legionella effector RavZ using semisynthetic LC3 proteins[J].eLife,2017，6:e23905.
[49] OMOTADE T O,ROY C R.Legionella pneumophila excludes autophagy adaptors from the ubiquitin-labeled vacuole in which it resides[J].Infection and Immunity,2020，88(8):e00793-19.
[50] GE J,WANG Y,CHEN X,et al.Phosphoribosyl-linked serine ubiquitination of USP14 by the SidE family effectors of Legionella excludes p62 from the bacterial phagosome[J].Cell Reports,2023，42(8):112817.
[51] LIN M,LIU H,XIONG Q,et al.Ehrlichia secretes Etf-1 to induce autophagy and capture nutrients for its growth through RAB5 and class Ⅲ phosphatidylinositol 3-kinase[J].Autophagy,2016,12(11):2145-2166.
[52] LINA TT,LUO T,VELAYUTHAM T S,et al.Ehrlichia activation of Wnt-PI3K-mTOR signaling inhibits autolysosome generation and autophagic destruction by the mononuclear phagocyte[J].Infection and Immunity,2017，85(12):e00690-17.
[53] DAVID L,TAIEB F,PÉNARY M,et al.Outer membrane vesicles produced by pathogenic strains of Escherichia coli block autophagic flux and exacerbate inflammasome activation[J].Autophagy,2022,18(12):2913-2925.
[54] 张宇.以HlyA依赖的细胞自噬的增强促进尿路致病性大肠杆菌的排出[D].郑州：郑州大学,2020. ZHANG Y.Enhancement of HlyA-dependent autophagy promotes the excretion of pathogenic Escherichia coli in urinary tract[D].Zhengzhou:Zhengzhou University,2020.(in Chinese)
[55] 李晶祥.效应因子NleE抑制PSMD10二聚化调控宿主自噬[D].成都:四川大学,2020. LI J X.The bacterial effector NleE inhibits autophagy by blocking PSMD10 homodimerization[D].Chengdu:Sichuan University,2020.(in Chinese)
[56] DA SILVA A,DALMASSO G,LARABI A,et al.Identification of autophagy receptors for the Crohn’s disease-associated adherent-invasive Escherichia coli[J].Frontiers in Microbiology， 2024，14:1268243.
[57] XUE Y,DU M,SHENG H,et al.Escherichia coli O157∶H7 suppresses host autophagy and promotes epithelial adhesion via TIR-mediated and cAMP-independent activation of protein kinase A[J].Cell Death Discovery,2017,3:17055.
[58] 曹家敏,朱艳芳,华明明,等.铜绿假单胞菌胞外多糖生物合成与降解的研究进展[J/OL].生物技术,2025.[2025-03-20].http://kns.cnki.net/kcms/detail/23.1319.Q.20250301.2129.028.html. CAO J M,ZHU Y F,HUA M M,et al.Research progress on biosynthesis and degradation of exopolysaccharides from Pseudomonas aeruginosa[J/OL].Biotechnology,2025.[2025-03-20].http://kns.cnki.net/kcms/detail/23.1319.Q.20250301.2129.028.html.(in Chinese)
[59] 张长文.铜绿假单胞菌分泌蛋白Pec1通过抑制肺泡巨噬细胞自噬影响细菌清除效应的初步研究[D].南京：南京医科大学,2023. ZHANG C W.The effect of Pec1 secreted by Pseudomonas aeruginosa on bacterial clearance by inhibiting autophagy in alveolar macrophage[D].Nanjing:Nanjing Medical University,2023.(in Chinese)
[60] RAO L,DE LA ROSA I,XU Y,et al.Pseudomonas aeruginosa survives in epithelia by ExoS-mediated inhibition of autophagy and mTOR[J].EMBO Reports，2021，22(2):e50613.
[61] HARDY K S,TUCKEY A N,HOUSLEY N A,et al.The Pseudomonas aeruginosa type Ⅲ secretion system exoenzyme effector exoU induces mitochondrial damage in a murine bone marrow-derived macrophage infection mwodel[J].Infection and Immunity，2022，90(3):e0047021.
[62] ZHANG F,CHEN C,HU J,et al.Molecular mechanism of Helicobacter pylori-induced autophagy in gastric cancer[J]. Oncology Letters，2019，8(6):6221-6227.
[63] NABAVI-RAD A,YADEGAR A,SADEGHI A,et al.The interaction between autophagy, Helicobacter pylori,and gut microbiota in gastric carcinogenesis[J].Trends in Microbiology，2023，31(10):1024-1043.