分枝杆菌肝素结合血凝素研究进展

doi:10.19982/j.issn.1000-6621.20210593

摘要/Abstract

摘要：

结核病是由分枝杆菌感染引起的世界范围内流行的人畜共患病。肝素结合血凝素(heparin-binding adhesin,HBHA)是分枝杆菌表达的一种蛋白质,致病性分枝杆菌的HBHA蛋白具有黏附上皮细胞、扩散感染范围等功能。其发挥黏附功能的C端结构域能够刺激机体产生有效的Th1细胞免疫反应;HBHA特异的黏膜免疫反应能够提供一定的保护效果。这提示HBHA具有制作为疫苗的潜力。而且,HBHA蛋白在活动性结核病患者和潜伏感染者中引发的免疫反应存在差异,这使其可以成为新的诊断抗原。此外,在细胞水平上,HBHA可以利用补体系统进入巨噬细胞,促使巨噬细胞向M1极化,同时能够逃避自噬并诱发线粒体损伤和内质网应激介导功能,这为结核病的致病机制提供了更多的解释。HBHA与宿主之间相互作用认识的积累,可以为HBHA的应用性研究提供依据。

关键词: 分枝杆菌属, 肝素结合血凝素, 抗原, 研究

Abstract:

Tuberculosis is a worldwide zoonosis caused by mycobacteria. Heparin-binding adhesin (HBHA) is a protein produced by mycobacteria, with which the pathogenic strains can attach to epithelium cells and be disseminated to extra-pulmonary organs from lungs. The C terminal domain of it can induce Th1 responses of the body efficiently and a certain level of mucosal immune responses, suggesting its potential for developing a vaccine. Furthermore, the HBHA-specific immune responses in active tuberculosis patients differentiate from that in latent tuberculosis patients which indicates that it may work as a diagnostic antigen. At cellular level, HBHA can intrude into macrophages through complement receptors and turn them to M1 state while escaping from autophagy and triggering mitocondrial damage and endoplasmic reticulum stress. All of these provides more explanations for pathogenesis of tuberculosis. The constantly updated understanding of the interactions between HBHA and the host will provide inspirations for the application study of exploiting its immunogenic potential.

Key words: Mycobacterium, Heparin-binding hemagglutinin adhesins, Antigen, Research

中图分类号:

R378.91

陈玉兰, 刘一朵, 周向梅. 分枝杆菌肝素结合血凝素研究进展[J]. 中国防痨杂志, 2022, 44(1): 95-101. doi: 10.19982/j.issn.1000-6621.20210593

CHEN Yu-lan, LIU Yi-duo, ZHOU Xiang-mei. A review of researches on heparin-binding adhesions of Mycobacteria[J]. Chinese Journal of Antituberculosis, 2022, 44(1): 95-101. doi: 10.19982/j.issn.1000-6621.20210593

图/表 2

参考文献 59

[1]	World Health Organization. Global tuberculosis report 2021. Geneva: World Health Orgnization, 2021.
[2]	Squeglia F, Ruggiero A, De Simone A, et al. A structural overview of mycobacterial adhesins: Key biomarkers for diagnostics and therapeutics. Protein Sci, 2018, 27(2):369-380. doi: 10.1002/pro.3346. doi: 10.1002/pro.3346 pmid: 29139177
[3]	Menozzi FD, Rouse JH, Alavi M, et al. Identification of a heparin-binding hemagglutinin present in mycobacteria. J Exp Med, 1996, 184(3):993-1001. doi: 10.1084/jem.184.3.993. doi: 10.1084/jem.184.3.993 URL
[4]	Huang TY, Irene D, Zulueta MM, et al. Structure of the Complex between a Heparan Sulfate Octasaccharide and Mycobacterial Heparin-Binding Hemagglutinin. Angew Chem Int Ed Engl, 2017, 56(15):4192-4196. doi: 10.1002/anie.201612518. doi: 10.1002/anie.201612518 URL
[5]	Parada C, Neri-Badillo IC, Vallecillo AJ, et al. New Insights into the Methylation of Mycobacterium tuberculosis Heparin Binding Hemagglutinin Adhesin Expressed in Rhodococcus erythropolis. Pathogens, 2021, 10(9):1139. doi: 10.3390/pathogens10091139. doi: 10.3390/pathogens10091139 URL
[6]	Menozzi FD, Bischoff R, Fort E, et al. Molecular characterization of the mycobacterial heparin-binding hemagglutinin, a mycobacterial adhesin. Proc Natl Acad Sci U S A, 1998, 95(21):12625-12630. doi: 10.1073/pnas.95.21.12625. doi: 10.1073/pnas.95.21.12625 pmid: 9770536
[7]	Raman S, Vernon R, Thompson J, et al. Structure prediction for CASP8 with all-atom refinement using Rosetta. Proteins, 2009, 77 Suppl 9(9): 89-99. doi: 10.1002/prot.22540. doi: 10.1002/prot.22540 URL
[8]	Song Y, DiMaio F, Wang RY , et al. High-resolution compara-tive modeling with RosettaCM. Structure, 2013, 21(10):1735-1742. doi: 10.1016/j.str.2013.08.005. doi: 10.1016/j.str.2013.08.005 URL
[9]	Kim Y, Cuff M, Hendricks R, et al. Crystal Structure of a Basic Coiled-Coil Protein of Unknown Function from Eubacterium eligens ATCC 27750. Illinois State: Midwest Center for Structural Genomics, 2009.
[10]	Ko J, Park H, Heo L, et al. GalaxyWEB server for protein structure prediction and refinement. Nucleic Acids Res, 2012, 40(Web Server issue):W294-297. doi: 10.1093/nar/gks493. doi: 10.1093/nar/gks493 URL
[11]	Dupres V, Menozzi FD, Locht C, et al. Nanoscale mapping and functional analysis of individual adhesins on living bacteria. Nat Methods, 2005, 2(7):515-520. doi: 10.1038/nmeth769. doi: 10.1038/nmeth769
[12]	Delogu G, Sanguinetti M, Posteraro B, et al. The hbhA gene of Mycobacterium tuberculosis is specifically upregulated in the lungs but not in the spleens of aerogenically infected mice. Infect Immun, 2006, 74(5):3006-3011. doi: 10.1128/IAI.74.5.3006-3011.2006. doi: 10.1128/IAI.74.5.3006-3011.2006 URL
[13]	Veyron-Churlet R, Dupres V, Saliou JM, et al. Rv0613c/MSMEG_1285 Interacts with HBHA and Mediates Its Proper Cell-Surface Exposure in Mycobacteria. Int J Mol Sci, 2018, 19(6):1673. doi: 10.3390/ijms19061673. doi: 10.3390/ijms19061673 URL
[14]	Lanfranconi MP, Arabolaza A, Gramajo H, et al. Insights into the evolutionary history of the virulent factor HBHA of Mycobacterium tuberculosis. Arch Microbiol, 2021, 203(5):2171-2182. doi: 10.1007/s00203-021-02192-y. doi: 10.1007/s00203-021-02192-y pmid: 33620522
[15]	Lefrancois LH, Bodier CC, Cochard T, et al. Novel feature of Mycobacterium avium subsp. paratuberculosis, highlighted by characterization of the heparin-binding hemagglutinin adhesin. J Bacteriol, 2013, 195(21):4844-4853. doi: 10.1128/JB.00671-13. doi: 10.1128/JB.00671-13 pmid: 23974028
[16]	Menozzi FD, Reddy VM, Cayet D, et al. Mycobacterium tuberculosis heparin-binding haemagglutinin adhesin (HBHA) triggers receptor-mediated transcytosis without altering the integrity of tight junctions. Microbes Infect, 2006, 8(1):1-9. doi: 10.1016/j.micinf.2005.03.023. doi: 10.1016/j.micinf.2005.03.023 pmid: 15914062
[17]	赵子惠. 牛分枝杆菌肝素结合血凝素(HBHA)的黏附功能鉴定. 兰州:甘肃农业大学, 2016.
[18]	Sechi LA, Ahmed N, Felis GE, et al. Immunogenicity and cytoadherence of recombinant heparin binding haemagglutinin (HBHA) of Mycobacterium avium subsp. paratuberculosis: functional promiscuity or a role in virulence? Vaccine, 2006, 24(3):236-243. doi: 10.1016/j.vaccine.2005.11.030. doi: 10.1016/j.vaccine.2005.11.030 URL
[19]	de Lima CS, Marques MA, Debrie AS, et al. Heparin-binding hemagglutinin (HBHA) of Mycobacterium leprae is expressed during infection and enhances bacterial adherence to epithelial cells. FEMS Microbiol Lett, 2009, 292(2):162-169. doi: 10.1111/j.1574-6968.2009.01488.x. doi: 10.1111/j.1574-6968.2009.01488.x URL
[20]	Pethe K, Alonso S, Biet F, et al. The heparin-binding haemag-glutinin of M.tuberculosis is required for extrapulmonary dissemination. Nature, 2001, 412(6843):190-194. doi: 10.1038/35084083. doi: 10.1038/35084083 URL
[21]	Ryndak MB, Chandra D, Laal S. Understanding dissemination of Mycobacterium tuberculosis from the lungs during primary infection. J Med Microbiol, 2016, 65(5):362-369. doi: 10.1099/jmm.0.000238. doi: 10.1099/jmm.0.000238 URL
[22]	Sarrazin S, Lamanna WC, Esko JD. Heparan sulfate proteoglycans. Cold Spring Harb Perspect Biol, 2011, 3(7):a004952. doi: 10.1101/cshperspect.a004952. doi: 10.1101/cshperspect.a004952
[23]	Aquino RS, Teng YH, Park PW. Glycobiology of syndecan-1 in bacterial infections. Biochem Soc Trans, 2018, 46(2):371-377. doi: 10.1042/BST20170395. doi: 10.1042/BST20170395 URL
[24]	Raze D, Verwaerde C, Deloison G, et al. Heparin-Binding Hemagglutinin Adhesin (HBHA) Is Involved in Intracytosolic Lipid Inclusions Formation in Mycobacteria. Front Microbiol, 2018, 9:2258. doi: 10.3389/fmicb.2018.02258. doi: 10.3389/fmicb.2018.02258 URL
[25]	Veyron-Churlet R, Saliou JM, Locht C. Interconnection of the mycobacterial heparin-binding hemagglutinin with cholesterol degradation and heme/iron pathways identified by proximity-dependent biotin identification in Mycobacterium smegmatis. Environ Microbiol, 2021, 23(6):3212-3224. doi: 10.1111/1462-2920.15547. doi: 10.1111/1462-2920.15547 pmid: 33913567
[26]	Armstrong RM, Carter DC, Atkinson SN, et al. Association of Mycobacterium Proteins with Lipid Droplets. J Bacteriol, 2018, 200(16):e00240-18. doi: 10.1128/JB.00240-18. doi: 10.1128/JB.00240-18
[27]	范琳琳. 结核分枝杆菌HBHA和ESAT-6对巨噬细胞极化作用的研究. 西安: 中国人民解放军空军军医大学, 2018.
[28]	Esteban J, García-Coca M. Mycobacterium Biofilms. Front Microbiol, 2018, 8:2651. doi: 10.3389/fmicb.2017.02651. doi: 10.3389/fmicb.2017.02651 URL
[29]	Mueller-Ortiz SL, Wanger AR, Norris SJ. Mycobacterial protein HbhA binds human complement component C3. Infect Immun, 2001, 69(12):7501-7511. doi: 10.1128/IAI.69.12.7501-7511.2001. doi: 10.1128/IAI.69.12.7501-7511.2001 pmid: 11705926
[30]	Zheng Q, Li Z, Zhou S, et al. Heparin-binding Hemagglutinin of Mycobacterium tuberculosis Is an Inhibitor of Autophagy. Front Cell Infect Microbiol, 2017, 7:33. doi: 10.3389/fcimb.2017.00033. doi: 10.3389/fcimb.2017.00033
[31]	Choi JA, Lim YJ, Cho SN, et al. Mycobacterial HBHA induces endoplasmic reticulum stress-mediated apoptosis through the generation of reactive oxygen species and cytosolic Ca2+ in murine macrophage RAW 264.7 cells. Cell Death Dis, 2013, 4(12):e957. doi: 10.1038/cddis.2013.489. doi: 10.1038/cddis.2013.489 URL
[32]	Kim KH, Yang CS, Shin AR, et al. Mycobacterial Heparin-binding Hemagglutinin Antigen Activates Inflammatory Responses through PI3-K/Akt, NF-κB, and MAPK Pathways. Immune Netw, 2011, 11(2):123-133. doi: 10.4110/in.2011.11.2.123. doi: 10.4110/in.2011.11.2.123 pmid: 21637390
[33]	Hougardy JM, Schepers K, Place S, et al. Heparin-binding-hemagglutinin-induced IFN-gamma release as a diagnostic tool for latent tuberculosis. PLoS One, 2007, 2(10):e926. doi: 10.1371/journal.pone.0000926. doi: 10.1371/journal.pone.0000926 URL
[34]	Sali M, Buonsenso D, D’Alfonso P , et al. Combined use of Quantiferon and HBHA-based IGRA supports tuberculosis diagnosis and therapy management in children. J Infect, 2018, 77(6):526-533. doi: 10.1016/j.jinf.2018.09.011. doi: 10.1016/j.jinf.2018.09.011 URL
[35]	Wen HL, Li CL, Li G, et al. Involvement of methylated HBHA expressed from Mycobacterium smegmatis in an IFN-γ release assay to aid discrimination between latent infection and active tuberculosis in BCG-vaccinated populations. Eur J Clin Microbiol Infect Dis, 2017, 36(8):1415-1423. doi: 10.1007/s10096-017-2948-1. doi: 10.1007/s10096-017-2948-1 URL
[36]	聂理会, 孙兆刚, 张旭霞, 等. 结核分枝杆菌肝素结合血凝素在肺结核及肺外结核中的免疫作用研究. 中国防痨杂志, 2009, 31(9):544-547.
[37]	Yamashita Y, Oe T, Kawakami K, et al. CD4⁺ T Responses Other Than Th1 Type Are Preferentially Induced by Latency-Associated Antigens in the State of Latent Mycobacterium tuberculosis Infection. Front Immunol, 2019, 10:2807. doi: 10.3389/fimmu.2019.02807. doi: 10.3389/fimmu.2019.02807 pmid: 31849981
[38]	Masungi C, Temmerman S, Van Vooren JP, et al. Differential T and B cell responses against Mycobacterium tuberculosis heparin-binding hemagglutinin adhesin in infected healthy individuals and patients with tuberculosis. J Infect Dis, 2002, 185(4):513-520. doi: 10.1086/338833. doi: 10.1086/338833 URL
[39]	Hougardy JM, Place S, Hildebrand M, et al. Regulatory T cells depress immune responses to protective antigens in active tuberculosis. Am J Respir Crit Care Med, 2007, 176(4):409-416. doi: 10.1164/rccm.200701-084OC. doi: 10.1164/rccm.200701-084OC URL
[40]	Place S, Verscheure V, de San N, et al. Heparin-binding, hemagglutinin-specific IFN-gamma synthesis at the site of infection during active tuberculosis in humans. Am J Respir Crit Care Med, 2010, 182(6):848-854. doi: 10.1164/rccm.201001-0083OC. doi: 10.1164/rccm.201001-0083OC URL
[41]	Temmerman ST, Place S, Debrie AS, et al. Effector functions of heparin-binding hemagglutinin-specific CD8⁺ T lymphocytes in latent human tuberculosis. J Infect Dis, 2005, 192(2):226-232. doi: 10.1086/430930. doi: 10.1086/430930 pmid: 15962217
[42]	Jung ID, Jeong SK, Lee CM, et al. Enhanced efficacy of therapeutic cancer vaccines produced by co-treatment with Mycobacterium tuberculosis heparin-binding hemagglutinin, a novel TLR4 agonist. Cancer Res, 2011, 71(8):2858-2870. doi: 10.1158/0008-5472.CAN-10-3487. doi: 10.1158/0008-5472.CAN-10-3487 pmid: 21368092
[43]	Temmerman S, Pethe K, Parra M, et al. Methylation-dependent T cell immunity to Mycobacterium tuberculosis heparin-binding hemagglutinin. Nat Med, 2004, 10(9):935-941. doi: 10.1038/nm1090. doi: 10.1038/nm1090 pmid: 15300244
[44]	Corbière V, Segers J, Desmet R, et al. Natural T Cell Epitope Containing Methyl Lysines on Mycobacterial Heparin-Binding Hemagglutinin. J Immunol, 2020, 204(7):1715-1723. doi: 10.4049/jimmunol.1901214. doi: 10.4049/jimmunol.1901214 URL
[45]	Kohama H, Umemura M, Okamoto Y, et al. Mucosal immunization with recombinant heparin-binding haemagglutinin adhesin suppresses extrapulmonary dissemination of Mycobacterium bovis bacillus Calmette-Guérin (BCG) in infected mice. Vaccine, 2008, 26(7):924-932. doi: 10.1016/j.vaccine.2007.12.005. doi: 10.1016/j.vaccine.2007.12.005 URL
[46]	Fukui M, Shinjo K, Umemura M, et al. Enhanced effect of BCG vaccine against pulmonary Mycobacterium tuberculosis infection in mice with lung Th17 response to mycobacterial heparin-binding hemagglutinin adhesin antigen. Microbiol Immunol, 2015, 59(12):735-743. doi: 10.1111/1348-0421.12340. doi: 10.1111/1348-0421.12340 URL
[47]	Rouanet C, Debrie AS, Lecher S, et al. Subcutaneous boosting with heparin binding haemagglutinin increases BCG-induced protection against tuberculosis. Microbes Infect, 2009, 11(13):995-1001. doi: 10.1016/j.micinf.2009.07.005. doi: 10.1016/j.micinf.2009.07.005 pmid: 19635582
[48]	Parra M, Pickett T, Delogu G, et al. The mycobacterial heparin-binding hemagglutinin is a protective antigen in the mouse aerosol challenge model of tuberculosis. Infect Immun, 2004, 72(12):6799-6805. doi: 10.1128/IAI.72.12.6799-6805.2004. doi: 10.1128/IAI.72.12.6799-6805.2004 URL
[49]	Belay M, Legesse M, Mihret A, et al. IFN-γ and IgA against non-methylated heparin-binding hemagglutinin as markers of protective immunity and latent tuberculosis: Results of a longitudinal study from an endemic setting. J Infect, 2016, 72(2):189-200. doi: 10.1016/j.jinf.2015.09.040. doi: 10.1016/j.jinf.2015.09.040 URL
[50]	Breedveld A, van Egmond M. IgA and FcαRI: Pathological Roles and Therapeutic Opportunities. Front Immunol, 2019, 10:553. doi: 10.3389/fimmu.2019.00553. doi: 10.3389/fimmu.2019.00553 pmid: 30984170
[51]	Tang J, Huang Y, Jiang S, et al. QuantiFERON-TB Gold Plus combined with HBHA-Induced IFN-γ release assay improves the accuracy of identifying tuberculosis disease status. Tuberculosis (Edinb), 2020, 124:101966. doi: 10.1016/j.tube.2020.101966. doi: 10.1016/j.tube.2020.101966
[52]	Chedid C, Kokhreidze E, Tukvadze N, et al. Relevance of QuantiFERON-TB Gold Plus and Heparin-Binding Hemagglutinin Interferon-γ Release Assays for Monitoring of Pulmonary Tuberculosis Clearance: A Multicentered Study. Front Immunol, 2021, 11:616450. doi: 10.3389/fimmu.2020.616450. doi: 10.3389/fimmu.2020.616450
[53]	Dreesman A, Corbière V, Libin M, et al. Specific Host Signatures for the Detection of Tuberculosis Infection in Children in a Low TB Incidence Country. Front Immunol, 2021, 12:575519. doi: 10.3389/fimmu.2021.575519. doi: 10.3389/fimmu.2021.575519
[54]	Benhadou F, Dirix V, Domont F, et al. Tuberculosis Risk Stratification of Psoriatic Patients Before Anti-TNF-α Treatment. Front Immunol, 2021, 12:672894. doi: 10.3389/fimmu.2021.672894. doi: 10.3389/fimmu.2021.672894
[55]	Lei Y, Shao J, Ma F, et al. Enhanced efficacy of a multi-epitope vaccine for type A and O foot and-mouth disease virus by fusing multiple epitopes with Mycobacterium tuberculosis heparin-binding hemagglutinin (HBHA), a novel TLR4 agonist. Mol Immunol, 2020, 121:118-126. doi: 10.1016/j.molimm.2020.02.018. doi: 10.1016/j.molimm.2020.02.018 URL
[56]	Vivekanandam R, Rajagopalan K, Jeevanandam M, et al. Designing of cytotoxic T lymphocyte-based multi-epitope vaccine against SARS-CoV2: a reverse vaccinology approach. J Biomol Struct Dyn, 2021: 1-16. doi: 10.1080/07391102.2021.1993338. doi: 10.1080/07391102.2021.1993338
[57]	Muhammad SA, Ashfaq H, Zafar S, et al. Polyvalent therapeutic vaccine for type 2 diabetes mellitus: Immunoinformatics approach to study co-stimulation of cytokines and GLUT1 receptors. BMC Mol Cell Biol, 2020, 21(1):56. doi: 10.1186/s12860-020-00279-w. doi: 10.1186/s12860-020-00279-w URL
[58]	Copland A, Diogo GR, Hart P, et al. Mucosal Delivery of Fusion Proteins with Bacillus subtilis Spores Enhances Protection against Tuberculosis by Bacillus Calmette-Guérin. Front Immunol, 2018, 9:346. doi: 10.3389/fimmu.2018.00346. doi: 10.3389/fimmu.2018.00346 URL
[59]	Hart P, Copland A, Diogo GR, et al. Nanoparticle-Fusion Protein Complexes Protect against Mycobacterium tuberculosis Infection. Mol Ther, 2018, 26(3):822-833. doi: 10.1016/j.ymthe.2017.12.016. doi: 10.1016/j.ymthe.2017.12.016 URL