留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

抗菌肽作为免疫调节剂治疗细菌感染的潜力

梁国柱 阮诗媚 何艳梅 杨海龙

梁国柱, 阮诗媚, 何艳梅, 杨海龙. 抗菌肽作为免疫调节剂治疗细菌感染的潜力[J]. 昆明医科大学学报, 2023, 44(10): 189-195. doi: 10.12259/j.issn.2095-610X.S20231013
引用本文: 梁国柱, 阮诗媚, 何艳梅, 杨海龙. 抗菌肽作为免疫调节剂治疗细菌感染的潜力[J]. 昆明医科大学学报, 2023, 44(10): 189-195. doi: 10.12259/j.issn.2095-610X.S20231013
Guozhu LIANG, Shimei RUAN, Yanmei HE, Hailong YANG. Prospects of Antimicrobial Peptides as Immunomodulators in the Treatment of Bacterial Infections[J]. Journal of Kunming Medical University, 2023, 44(10): 189-195. doi: 10.12259/j.issn.2095-610X.S20231013
Citation: Guozhu LIANG, Shimei RUAN, Yanmei HE, Hailong YANG. Prospects of Antimicrobial Peptides as Immunomodulators in the Treatment of Bacterial Infections[J]. Journal of Kunming Medical University, 2023, 44(10): 189-195. doi: 10.12259/j.issn.2095-610X.S20231013

抗菌肽作为免疫调节剂治疗细菌感染的潜力

doi: 10.12259/j.issn.2095-610X.S20231013
基金项目: 国家自然科学基金资助项目(82372259);云南省科技厅科技计划基金资助项目(202301AY070001-015)
详细信息
    作者简介:

    梁国柱(1995~),男,山西忻州人,医学硕士,主要从事抗菌肽的结构与功能研究工作

    杨海龙,博士,教授,博士生导师,云南省中青年学术和技术带头人,主要从事免疫调节肽与抗感染研究。以第一或通讯(含共同第一或通讯)作者发表SCI收录研究论文22篇,包括eLife、 ACS infectious dieases、Molecular & Cellular Proteomics、Free RadicBiol Med、Biochemical Journal和Parasit Vectors等期刊。以第一发明人获授权的国家发明专利4项。主持国家自然科学基金4项(面上项目3项,地区基金1项),主持云南省科技厅-昆明医科大学应用基础研究联合重点项目1项。2019年获云南省自然科学一等奖(排名第4),2010年获云南省自然科学二等奖(排名第2)

    通讯作者:

    杨海龙,E-mail:jxauyhl@aliyun.com

  • 中图分类号: R392.11

Prospects of Antimicrobial Peptides as Immunomodulators in the Treatment of Bacterial Infections

  • 摘要: 自1928年青霉素被用于治疗细菌感染性疾病以来,抗生素拯救了无数患者的生命。然而,随着细菌抗药性的增加,细菌感染性疾病的临床治疗变得愈发困难。抗菌肽因其功能广泛且毒副作用低等特点,被认为是理想的传统抗生素替代品。其中,一些具有免疫调节功能的抗菌肽能够调节机体自身的固有免疫和获得性免疫反应,直接靶向机体免疫系统而非病原微生物,从而避免对病原微生物的选择压力,不易产生耐药性,在抗感染治疗方面具有广阔的应用价值。将从抗菌肽的免疫调节活性、临床治疗中的应用潜力以及局限性等方面进行概述,为新型抗生素的开发利用提供新的视野。
  • 图  1  抗菌肽的免疫调节活性

    Figure  1.  Immunomodulatory activity of AMPs

  • [1] Zasloff M. Antimicrobial peptides of multicellular organisms[J]. Nature,2002,415(6870):389-395. doi: 10.1038/415389a
    [2] Hancock R E,Nijnik A,Philpott D J. Modulating immunity as a therapy for bacterial infections[J]. Nat Rev Microbiol,2012,10(4):243-254. doi: 10.1038/nrmicro2745
    [3] Hamill P,Brown K,Jenssen H,et al. Novel anti-infectives: Is host defence the answer?[J]. Curr Opin Biotechnol,2008,19(6):628-636. doi: 10.1016/j.copbio.2008.10.006
    [4] Blyth G a D,Connors L,Fodor C,et al. The network of colonic host defense peptides as an innate immune defense against enteropathogenic bacteria[J]. Front Immunol,2020,11(15):965.
    [5] Shelley J R,Davidson D J,Dorin J R. The dichotomous responses driven by β-defensins[J]. Front Immunol,2020,11(56):1176.
    [6] Wu D,Fu L,Wen W,et al. The dual antimicrobial and immunomodulatory roles of host defense peptides and their applications in animal production[J]. Anim Sci Biotechnol,2022,13(1):141. doi: 10.1186/s40104-022-00796-y
    [7] Buccini D F,Cardoso M H,Franco O L. Antimicrobial peptides and cell-penetrating peptides for treating intracellular bacterial infections[J]. Front Cell Infect Microbiol,2021,10:612931. doi: 10.3389/fcimb.2020.612931
    [8] Bowdish D M,Davidson D J,Lau Y E,et al. Impact of LL-37 on anti-infective immunity[J]. J Leukoc Biol,2005,77(4):451-459.
    [9] Brown K L,Hancock R E. Cationic host defense (antimicrobial) peptides[J]. Curr Opin Immunol,2006,18(1):24-30. doi: 10.1016/j.coi.2005.11.004
    [10] Döring Y,Libby P,Soehnlein O. Neutrophil extracellular traps participate in cardiovascular diseases:Recent experimental and clinical insights[J]. Circ Res,2020,126(9):1228-1241. doi: 10.1161/CIRCRESAHA.120.315931
    [11] Alford M A,Baquir B,Santana F L,et al. Cathelicidin host defense peptides and inflammatory signaling:Striking a balance[J]. Front Microbiol,2020,11:1902. doi: 10.3389/fmicb.2020.01902
    [12] Territo M C,Ganz T,Selsted M E,et al. Monocyte-chemotactic activity of defensins from human neutrophils[J]. J Clin Invest,1989,84(6):2017-2020. doi: 10.1172/JCI114394
    [13] Hölzl M A,Hofer J,Steinberger P,et al. Host antimicrobial proteins as endogenous immunomodulators[J]. Immunol Lett,2008,119(1-2):4-11. doi: 10.1016/j.imlet.2008.05.003
    [14] Van Harten R M,Van Woudenbergh E,Van Dijk A,et al. Cathelicidins: Immunomodulatory antimicrobials[J]. Vaccines (Basel),2018,6(3):1-23.
    [15] Zughaier S M,Shafer W M,Stephens D S. Antimicrobial peptides and endotoxin inhibit cytokine and nitric oxide release but amplify respiratory burst response in human and murine macrophages[J]. Cell Microbiol,2005,7(9):1251-1262. doi: 10.1111/j.1462-5822.2005.00549.x
    [16] Cai J,Cui X,Wang X,et al. A Novel anti-infective peptide BCCY-1 with immunomodulatory activities[J]. Front Immunol,2021,12:713960. doi: 10.3389/fimmu.2021.713960
    [17] Laman A G,Lathe R,Savinov G V,et al. Innate immunity: Bacterial cell-wall muramyl peptide targets the conserved transcription factor YB-1[J]. FEBS Lett,2015,589(15):1819-1824. doi: 10.1016/j.febslet.2015.05.028
    [18] Mookherjee N,Hancock R E. Cationic host defence peptides: Innate immune regulatory peptides as a novel approach for treating infections[J]. Cell Mol Life Sci,2007,64(7-8):922-933. doi: 10.1007/s00018-007-6475-6
    [19] Nijnik A,Hancock R. Host defence peptides: Antimicrobial and immunomodulatory activity and potential applications for tackling antibiotic-resistant infections[J]. Emerg Health Threats J,2009,2:e1.
    [20] Tjabringa G S,Ninaber D K,Drijfhout J W,et al. Human cathelicidin LL-37 is a chemoattractant for eosinophils and neutrophils that acts via formyl-peptide receptors[J]. Int Arch Allergy Immunol,2006,140(2):103-112. doi: 10.1159/000092305
    [21] De Y,Chen Q,Schmidt A P,et al. LL-37,the neutrophil granule and epithelial cell-derived cathelicidin,utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils,monocytes,and T cells[J]. J Exp Med,2000,192(7):1069-1074. doi: 10.1084/jem.192.7.1069
    [22] Niyonsaba F,Iwabuchi K,Someya A,et al. A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis[J]. Immunology,2002,106(1):20-26. doi: 10.1046/j.1365-2567.2002.01398.x
    [23] Yang D,Chen Q,Le Y,et al. Differential regulation of formyl peptide receptor-like 1 expression during the differentiation of monocytes to dendritic cells and macrophages[J]. J Immunol,2001,166(6):4092-4098. doi: 10.4049/jimmunol.166.6.4092
    [24] Lee H Y,Bae Y S. The anti-infective peptide,innate defense-regulator peptide,stimulates neutrophil chemotaxis via a formyl peptide receptor[J]. Biochem Biophys Res Commun,2008,369(2):573-578. doi: 10.1016/j.bbrc.2008.02.046
    [25] Scott M G,Dullaghan E,Mookherjee N,et al. An anti-infective peptide that selectively modulates the innate immune response[J]. Nat Biotechnol,2007,25(4):465-472. doi: 10.1038/nbt1288
    [26] Chen X,Takai T,Xie Yet al. Human antimicrobial peptide LL-37 modulates proinflammatory responses induced by cytokine milieus and double-stranded RNA in human keratinocytes[J]. Biochem Biophys Res Commun,2013,433(4):532-537. doi: 10.1016/j.bbrc.2013.03.024
    [27] Coorens M,Scheenstra M R,Veldhuizen E J,et al. Interspecies cathelicidin comparison reveals divergence in antimicrobial activity,TLR modulation,chemokine induction and regulation of phagocytosis[J]. Sci Rep,2017,7:40874. doi: 10.1038/srep40874
    [28] Bautista-Hernández L A,Gómez-Olivares J L,Buentello-Volante B,et al. Fibroblasts: The unknown sentinels eliciting immune responses against microorganisms[J]. Eur J Microbiol Immunol (Bp),2017,7(3):151-157. doi: 10.1556/1886.2017.00009
    [29] Li N,Yamasaki K,Saito R,et al. Alarmin function of cathelicidin antimicrobial peptide LL37 through IL-36γ induction in human epidermal keratinocytes[J]. J Immunol,2014,193(10):5140-5148.
    [30] Scott M G,Davidson D J,Gold M R,et al. The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses[J]. J Immunol,2002,169(7):3883-3891.
    [31] Moser M,Murphy K M. Dendritic cell regulation of TH1-TH2 development[J]. Nat Immunol,2000,1(3):199-205. doi: 10.1038/79734
    [32] Davidson D J,Currie A J,Reid G S,et al. The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization[J]. J Immunol,2004,172(2):1146-1156. doi: 10.4049/jimmunol.172.2.1146
    [33] Bandholtz L,Ekman G J,Vilhelmsson M,et al. Antimicrobial peptide LL-37 internalized by immature human dendritic cells alters their phenotype[J]. Scand J Immunol,2006,63(6):410-419. doi: 10.1111/j.1365-3083.2006.001752.x
    [34] Kim S H,Kim Y N,Jang Y S. Cutting Edge: LL-37-mediated formyl peptide receptor-2 signaling in follicular dendritic cells contributes to B cell activation in peyer's patch germinal centers[J]. J Immunol,2017,198(2):629-633. doi: 10.4049/jimmunol.1600886
    [35] Yu Y,Zhang Y,Zhang Y,et al. LL-37-induced human mast cell activation through G protein-coupled receptor MrgX2[J]. Int Immunopharmacol,2017,49:6-12. doi: 10.1016/j.intimp.2017.05.016
    [36] Gupta K,Subramanian H,Ali H. Modulation of host defense peptide-mediated human mast cell activation by LPS[J]. Innate Immun,2016,22(1):21-30. doi: 10.1177/1753425915610643
    [37] Subramanian H,Gupta K,Guo Q,et al. Mas-related gene X2 (MrgX2) is a novel G protein-coupled receptor for the antimicrobial peptide LL-37 in human mast cells: Resistance to receptor phosphorylation,desensitization,and internalization[J]. J Biol Chem,2011,286(52):44739-44749. doi: 10.1074/jbc.M111.277152
    [38] Rajakariar R,Hilliard M,Lawrence T,et al. Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxyDelta12 14 PGJ2[J]. Proc Natl Acad Sci U S A,2007,104(52):20979-20984. doi: 10.1073/pnas.0707394104
    [39] Zhang Y Y,Yu Y Y,Zhang Y R,et al. The modulatory effect of TLR2 on LL-37-induced human mast cells activation[J]. Biochem Biophys Res Commun,2016,470(2):368-374. doi: 10.1016/j.bbrc.2016.01.037
    [40] Andrés C M C,Pérez De La Lastra J M,Juan C A,et al. The role of reactive species on innate immunity[J]. Vaccines (Basel),2022,10(10):1735. doi: 10.3390/vaccines10101735
    [41] Yang B,Good D,Mosaiab T,et al. Significance of LL-37 on immunomodulation and disease outcome[J]. Biomed Res Int,2020,2020:8349712.
    [42] Yang Y,Jing W,Qiao L,et al. A non-bactericidal cathelicidin provides prophylactic efficacy against bacterial infection by driving phagocyte influx[J]. Elife,2022,11:e72849. doi: 10.7554/eLife.72849
    [43] Jinwei C,Xin C,Tiaofei Y,et al. Characterization and functional analysis of cathelicidin-MH,a novel frog-derived peptide with anti-septicemic properties[J]. Elife,2021,10:e64411. doi: 10.7554/eLife.64411
    [44] Yeung A T,Gellatly S L,Hancock R E. Multifunctional cationic host defence peptides and their clinical applications[J]. Cell Mol Life Sci,2011,68(13):2161-2176. doi: 10.1007/s00018-011-0710-x
    [45] Mookherjee N,Anderson M A,Haagsman H P,et al. Antimicrobial host defence peptides: Functions and clinical potential[J]. Nat Rev Drug Discov,2020,19(5):311-332. doi: 10.1038/s41573-019-0058-8
    [46] Mookherjee N,Brown K L,Bowdish D M,et al. Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37[J]. J Immunol,2006,176(4):2455-2464. doi: 10.4049/jimmunol.176.4.2455
    [47] Amatngalim G D,Nijnik A,Hiemstra P S,et al. Cathelicidin peptide LL-37 modulates TREM-1 expression and inflammatory responses to microbial compounds[J]. Inflammation,2011,34(5):412-425. doi: 10.1007/s10753-010-9248-6
    [48] Shaykhiev R,Sierigk J,Herr C,et al. The antimicrobial peptide cathelicidin enhances activation of lung epithelial cells by LPS[J]. Faseb J,2010,24(12):4756-4766. doi: 10.1096/fj.09-151332
    [49] Marin M,Holani R,Shah C B,et al. Cathelicidin modulates synthesis of Toll-like Receptors (TLRs) 4 and 9 in colonic epithelium[J]. Mol Immunol,2017,91:249-258. doi: 10.1016/j.molimm.2017.09.011
    [50] Choi K Y,Napper S,Mookherjee N. Human cathelicidin LL-37 and its derivative IG-19 regulate interleukin-32-induced inflammation[J]. Immunology,2014,143(1):68-80. doi: 10.1111/imm.12291
    [51] Niyonsaba F,Madera L,Afacan N,et al. The innate defense regulator peptides IDR-HH2,IDR-1002,and IDR-1018 modulate human neutrophil functions[J]. J Leukoc Biol,2013,94(1):159-170. doi: 10.1189/jlb.1012497
    [52] Kandler K,Shaykhiev R,Kleemann P,et al. The anti-microbial peptide LL-37 inhibits the activation of dendritic cells by TLR ligands[J]. Int Immunol,2006,18(12):1729-1736. doi: 10.1093/intimm/dxl107
    [53] Nijnik A,Pistolic J,Wyatt A,et al. Human cathelicidin peptide LL-37 modulates the effects of IFN-gamma on APCs[J]. J Immunol,2009,183(9):5788-5798. doi: 10.4049/jimmunol.0901491
    [54] Hilchie A L,Wuerth K,Hancock R E. Immune modulation by multifaceted cationic host defense (antimicrobial) peptides[J]. Nat Chem Biol,2013,9(12):761-768. doi: 10.1038/nchembio.1393
    [55] Luo Y,Song Y. Mechanism of antimicrobial peptides: Antimicrobial,anti-Inflammatory and antibiofilm activities[J]. Int J Mol Sci,2021,22(21):11401. doi: 10.3390/ijms222111401
    [56] Afacan N J,Yeung A T,Pena O M,et al. Therapeutic potential of host defense peptides in antibiotic-resistant infections[J]. Curr Pharm Des,2012,18(6):807-819. doi: 10.2174/138161212799277617
    [57] Vlieghe P,Lisowski V,Martinez J,et al. Synthetic therapeutic peptides: Science and Market[J]. Drug Discov Today,2010,15(1-2):40-56. doi: 10.1016/j.drudis.2009.10.009
    [58] Duarte-Mata D I,Salinas-Carmona M C. Antimicrobial peptides’ immune modulation role in intracellular bacterial infection[J]. Front Immunol,2023,14:1119574. doi: 10.3389/fimmu.2023.1119574
    [59] Abdi M,Mirkalantari S,Amirmozafari N. Bacterial resistance to antimicrobial peptides[J]. J Pept Sci,2019,25(11):e3210.
    [60] Jia F,Wang J,Peng J,et al. D-amino acid substitution enhances the stability of antimicrobial peptide polybia-CP[J]. Acta Biochim Biophys Sin (Shanghai),2017,49(10):916-925. doi: 10.1093/abbs/gmx091
    [61] Ting D S J,Beuerman R W,Dua H S,et al. Strategies in translating the therapeutic potentials of host defense peptides[J]. Front Immunol,2020,11:983. doi: 10.3389/fimmu.2020.00983
    [62] Rounds T,Straus S K. Lipidation of antimicrobial peptides as a design strategy for future alternatives to antibiotics[J]. Int J Mol Sci,2020,21(24):9692. doi: 10.3390/ijms21249692
    [63] Mahlapuu M,Håkansson J,Ringstad L,et al. Antimicrobial peptides: An emerging category of therapeutic agents[J]. Front Cell Infect Microbiol,2016,6:194.
    [64] Braun K,Pochert A,Lindén M,et al. Membrane interactions of mesoporous silica nanoparticles as carriers of antimicrobial peptides[J]. J Colloid Interface Sci,2016,475:161-170. doi: 10.1016/j.jcis.2016.05.002
    [65] Boge L,Bysell H,Ringstad L,et al. Lipid-Based liquid crystals as carriers for antimicrobial peptides:Phase behavior and antimicrobial effect[J]. Langmuir,2016,32(17):4217-4228. doi: 10.1021/acs.langmuir.6b00338
    [66] Silva J P,Gonçalves C,Costa C,et al. Delivery of LLKKK18 loaded into self-assembling hyaluronic acid nanogel for tuberculosis treatment[J]. J Control Release,2016,235:112-124. doi: 10.1016/j.jconrel.2016.05.064
    [67] D’angelo I,Casciaro B,Miro A,et al. Overcoming barriers in Pseudomonas aeruginosa lung infections: Engineered nanoparticles for local delivery of a cationic antimicrobial peptide[J]. Colloids Surf B Biointerfaces,2015,135:717-725. doi: 10.1016/j.colsurfb.2015.08.027
    [68] Sandreschi S,Piras A M,Batoni G,et al. Perspectives on polymeric nanostructures for the therapeutic application of antimicrobial peptides[J]. Nanomedicine (Lond),2016,11(13):1729-1744. doi: 10.2217/nnm-2016-0057
    [69] Abd El-Hack M E,El-Saadony M T,Shafi M E,et al. Antimicrobial and antioxidant properties of chitosan and its derivatives and their applications: A review[J]. Int J Biol Macromol,2020,164:2726-2744. doi: 10.1016/j.ijbiomac.2020.08.153
  • [1] 李由, 丁恒, 崔亮, 赵元曦, 展恩雨, 李兴国.  椎间孔镜治疗单节段非特异性腰椎间隙感染的效果分析, 昆明医科大学学报.
    [2] 章艳碧, 冯磊, 师瑞, 骆贝贝, 唐灵通, 曹慧颖, 毕千叶.  血液指标在革兰阳性球菌和阴性杆菌感染中的诊疗效能, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20231218
    [3] 田波, 刘俊, 李海雯, 宋炜, 陈海云, 孙建军.  艾滋病患者细菌性血流感染病原菌分布及耐药情况, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20220616
    [4] 杨雪婷, 张惠锋.  产超广谱β-内酰胺酶肠杆菌科细菌感染患者使用抗菌药物的药物评价, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20220621
    [5] 杨童欣, 王光, 徐蕊, 苏思维, 方克伟, 刘建和, 李炯明.  抗菌肽LL-37对尿路上皮细胞跨膜屏障功能破坏的作用, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20220806
    [6] 崔朴梅, 陈太方, 陈超, 梁永梅, 徐悦.  云南某医院2016年至2019年抗菌药物使用与常见细菌耐药性的相关性分析, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20211127
    [7] 肖艳, 米弘瑛, 胡建英, 刘宇.  基于新生儿临床抗感染治疗与细菌变迁的影响, 昆明医科大学学报.
    [8] 赵晓丽, 唐树荣, 王司辰, 钱净, 任宝军, 曾文, 胡大春.  COPD合并细菌感染患者的外周血免疫细胞变化, 昆明医科大学学报.
    [9] 王光, 杨童欣, 姜永明, 方克伟, 刘建和, 李炯明.  抗菌肽LL-37诱导大鼠膀胱壁肥大细胞的炎症反应, 昆明医科大学学报.
    [10] 陈墨, 周泽平.  IL-10与自身免疫病的研究进展, 昆明医科大学学报.
    [11] 田薇.  利拉鲁肽调节脂肪酸的β-氧化改善非酒精性脂肪肝病大鼠症状, 昆明医科大学学报.
    [12] 李玉华.  细菌性阴道炎与8种牙周可疑致病微生物感染的关系, 昆明医科大学学报.
    [13] 段万石.  胸部恶性肿瘤患者院内细菌真菌混合感染的临床特征, 昆明医科大学学报.
    [14] 卯建.  降钙素原、超敏C-反应蛋白和淀粉样蛋白检测在细菌性感染诊断中的应用价值, 昆明医科大学学报.
    [15] 高振华.  蛇毒抗菌肽OH-CATH在血浆环境中对大肠杆菌的抗菌作用, 昆明医科大学学报.
    [16] 李思熳.  蛇毒抗菌肽Cathelicidin对大肠杆菌抗菌性的研究, 昆明医科大学学报.
    [17] 王峰.  昆明医科大学微生物学与免疫学教研室,云南 昆明 650500, 昆明医科大学学报.
    [18] 袁聪.  甲泼尼龙对受损脊髓组织中抗菌肽相关基因表达的调节, 昆明医科大学学报.
    [19] 张才军.  结核清注射剂对小鼠免疫调节的实验研究, 昆明医科大学学报.
    [20] 刘文凤.  多发大面积褥疮合并莫拉氏细菌感染患者的护理治疗1例, 昆明医科大学学报.
  • 加载中
图(1)
计量
  • 文章访问数:  1656
  • HTML全文浏览量:  943
  • PDF下载量:  33
  • 被引次数: 0
出版历程
  • 收稿日期:  2023-07-09
  • 网络出版日期:  2023-09-07
  • 刊出日期:  2023-10-25

目录

    /

    返回文章
    返回