科微学术

微生物学通报

布鲁氏菌Ⅳ型分泌系统效应因子调控宿主细胞功能研究进展
作者:
基金项目:

中国农业科学院科技创新工程(CAAS-CSLPDCP-202403)


Progress in the regulation of host cell functions by Brucella type Ⅳ secretion system effectors
Author:
  • 摘要
  • | |
  • 访问统计
  • |
  • 参考文献 [62]
  • | | | |
  • 文章评论
    摘要:

    布鲁氏菌(Brucella)是一种全球广泛传播的人畜共患病原体,能够感染野生动物、家养动物及人类。为了在宿主体内建立并维持慢性感染,布鲁氏菌进化出了多种策略逃逸宿主的免疫应答机制,并且在细胞内大量繁殖。其核心机制主要依赖于Ⅳ型分泌系统(type Ⅳ secretion system, T4SS)及其分泌的效应因子。T4SS通过将效应因子直接注入宿主细胞内,调控宿主细胞的多种功能,从而帮助病原体逃避免疫监控、操纵宿主细胞内环境,并促进布鲁氏菌的生存与复制。本文综述了布鲁氏菌T4SS的结构与功能,以及T4SS效应因子在调控宿主细胞功能方面的最新研究进展,探讨了布鲁氏菌如何通过调节宿主细胞信号传导途径,实现对细胞内液泡的控制,并形成有利于细菌存活的复制生态位。这些研究进展为我们更好地理解布鲁氏菌感染的致病机制提供了新见解,并有助于开发更有效的预防和治疗策略来应对布鲁氏菌感染。

    Abstract:

    Brucella is a genus of globally widespread zoonotic pathogens capable of infecting wild animals, domestic animals, and humans. To establish and sustain chronic infections within the host, Brucella have evolved multiple strategies to evade host immune responses and extensively replicate in host cells, which primarily rely on the type Ⅳ secretion system (T4SS) and its secreted effectors. The T4SS functions by directly injecting effectors into host cells, modulating various host cell functions to help the pathogen evade immune surveillance, manipulate the intracellular environment, and promote its survival and replication. This article reviews the structure and function of the Brucella T4SS and the latest research progress in the role of Brucella T4SS effectors in regulating host cell functions, exploring how bacteria of Brucella manipulate host cell signaling pathways to control intracellular vacuole dynamics and establish a replicative niche conducive to bacterial survival. These advancements provide new insights into the pathogenesis of Brucella infections and aid in the development of more effective strategies for preventing and treating Brucella-related diseases.

    参考文献
    [1] 朱良全, 秦玉明, 丁家波. 我国家畜布鲁氏菌病防控面临形势及思考[J]. 中国兽医杂志, 2020, 56(6): 137-140.
    [2] PEREIRA CR, COTRIM de ALMEIDA JVF, CARDOSO de OLIVEIRA IR, FARIA de OLIVEIRA L, PEREIRA LJ, ZANGERÔNIMO MG, LAGE AP, DORNELES EMS. Occupational exposure to Brucella spp.: asystematic review and meta-analysis[J]. PLoS Neglected Tropical Diseases, 2020, 14(5): e0008164.
    [3] 谢士杰, 彭小薇, 冯宇, 许冠龙, 丁家波, 范学政. 布鲁氏菌逃避宿主免疫机制的研究进展[J]. 生命科学, 2019, 31(9): 871-878. XIE SJ, PENG XW, FENG Y, XU GL, DING JB, FAN XZ. Mechanism of Brucella evading from host immune response[J]. Chinese Bulletin of Life Sciences, 2019, 31(9): 871-878(in Chinese).
    [4] SUÁREZ-ESQUIVEL M, CHAVES-OLARTE E, MORENO E, GUZMÁN-VERRI C. Brucella genomics: macro and micro evolution[J]. International Journal of Molecular Sciences, 2020, 21(20): 7749.
    [5] de CARVALHO TP, Da SILVA LA, CASTANHEIRA TLL, de SOUZA TD, Da PAIXÃO TA, LAZARO-ANTON L, TSOLIS RM, SANTOS RL. Cell and tissue tropism of Brucella spp.[J]. Infection and Immunity, 2023, 91(5): e0006223.
    [6] YANG ZL, CHAI ZL, WANG X, ZHANG ZH, ZHANG FW, KANG FQ, LIU WT, REN HG, JIN Y, YUE JJ. Comparative genomic analysis provides insights into the genetic diversity and pathogenicity of the genus Brucella[J]. Frontiers in Microbiology, 2024, 15: 1389859.
    [7] LI ZQ, WANG SL, HAN JC, SHI CX, YANG GL, CUI YY, XI L, YIN SH, ZHANG H. Deletion of Brucella transcriptional regulator GntR10 regulated the expression of quorum sensing system and type IV secretion system effectors, which affected the activation of NF-κB[J]. Journal of Proteomics, 2023, 283: 104938.
    [8] LIU YF, DONG H, PENG XW, GAO Q, JIANG H, XU GL, QIN YM, NIU JR, SUN SJ, LI P, DING JB, CHEN RA. RNA-seq reveals the critical role of Lon protease in stress response and Brucella virulence[J]. Microbial Pathogenesis, 2019, 130: 112-119.
    [9] SAYERS S, LI L, ONG E, DENG SZ, FU GH, LIN Y, YANG B, ZHANG S, FA ZZ, ZHAO B, XIANG ZS, LI YQ, ZHAO XM, OLSZEWSKI MA, CHEN LN, HE YQ. Victors: a web-based knowledge base of virulence factors in human and animal pathogens[J]. Nucleic Acids Research, 2019, 47(D1): D693-D700.
    [10] 刘郁夫, 董浩, 孙石静, 陈瑞爱, 丁家波. 细菌Lon蛋白酶研究进展[J]. 微生物学通报, 2019, 46(7): 1706-1711. LIU YF, DONG H, SUN SJ, CHEN RA, DING JB. Research progress on bacterial Lon protease[J]. Microbiology China, 2019, 46(7): 1706-1711(in Chinese).
    [11] RIVAS-SOLANO O, NÚÑEZ-MONTERO K, ALTAMIRANO-SILVA P, RUIZ-VILLALOBOS N, BARQUERO-CALVO E, MORENO E, CHAVES-OLARTE E, GUZMÁN-VERRI C. A bvrR/bvrS Non-Polar Brucella abortus Mutant confirms the role of the two-component system BvrR/BvrS in virulence and membrane integrity[J]. Microorganisms, 2023, 11(8): 2014.
    [12] GUO XY, ZENG H, LI MJ, XIAO Y, GU GJ, SONG ZH, SHUAI XH, GUO JH, HUANG QZ, ZHOU B, CHU YF, JIAO HW. The mechanism of chronic intracellular infection with Brucella spp.[J]. Frontiers in Cellular and Infection Microbiology, 2023, 13: 1129172.
    [13] LIU YF, SUN JL, PENG XW, DONG H, QIN YM, SHEN QC, JIANG H, XU GL, FENG Y, SUN SJ, DING JB, CHEN RA. Deletion of the LuxR-type regulator VjbR in Brucella canis affects expression of type IV secretion system and bacterial virulence, and the mutant strain confers protection against Brucella canis challenge in mice[J]. Microbial Pathogenesis, 2020, 139: 103865.
    [14] CASANOVA A, LOW SH, QUÉBATTE M, SEDZICKI J, TSCHON T, KETTERER M, SMITH K, EMMENLAUER M, BEN-TEKAYA H, DEHIO C. A role for the VPS retromer in Brucella intracellular replication revealed by genomewide siRNA screening[J]. mSphere, 2019, 4(3): e00380-19.
    [15] BORGHESAN E, SMITH EP, MYENI S, BINDER K, KNODLER LA, CELLI J. A Brucella effector modulates the Arf6-Rab8a GTPase cascade to promote intravacuolar replication[J]. EMBO Journal, 2021, 40(19): e107664.
    [16] LUIZET JB, RAYMOND J, LACERDA TLS, BARBIEUX E, KAMBAREV S, BONICI M, LEMBO F, WILLEMART K, BORG JP, CELLI J, GÉRARD FCA, MURAILLE E, GORVEL JP, SALCEDO SP. The Brucella effector BspL targets the ER-associated degradation (ERAD) pathway and delays bacterial egress from infected cells[J]. Proceedings of the National Academy of Sciences of the United States of America, 2021, 118(32): e2105324118.
    [17] XIONG X, LI BW, ZHOU ZX, GU GJ, LI MJ, LIU J, JIAO HW. The VirB system plays a crucial role in Brucella intracellular infection[J]. International Journal of Molecular Sciences, 2021, 22(24): 13637.
    [18] VILLAMIL GIRALDO AM, MARY C, SIVANESAN D, BARON C. VirB6 and VirB10 from the Brucella type IV secretion system interact via the N-terminal periplasmic domain of VirB6[J]. FEBS Letters, 2015, 589(15): 1883-1889.
    [19] BERGÉ C, WAKSMAN G, TERRADOT L. Structural and molecular biology of type IV secretion systems[J]. Current Topics in Microbiology and Immunology, 2017, 413: 31-60.
    [20] TERRADOT L, BAYLISS R, OOMEN C, LEONARD GA, BARON C, WAKSMAN G. Structures of two core subunits of the bacterial type IV secretion system, VirB8 from Brucella suis and ComB10 from Helicobacter pylori[J]. Proceedings of the National Academy of Sciences of the United States of America, 2005, 102(12): 4596-4601.
    [21] PASCHOS A, PATEY G, SIVANESAN D, GAO C, BAYLISS R, WAKSMAN G, O’CALLAGHAN D, BARON C. Dimerization and interactions of Brucella suis VirB8 with VirB4 and VirB10 are required for its biological activity[J]. Proceedings of the National Academy of Sciences of the United States of America, 2006, 103(19): 7252-7257.
    [22] FRONZES R, CHRISTIE PJ, WAKSMAN G. The structural biology of type IV secretion systems[J]. Nature Reviews Microbiology, 2009, 7(10): 703-714.
    [23] HÖPPNER C, CARLE A, SIVANESAN D, HOEPPNER S, BARON C. The putative lytic transglycosylase VirB1 from Brucella suis interacts with the type IV secretion system core components VirB8, VirB9 and VirB11[J]. Microbiology, 2005, 151(Pt 11): 3469-3482.
    [24] WARD DV, DRAPER O, ZUPAN JR, ZAMBRYSKI PC. Peptide linkage mapping of the Agrobacterium tumefaciens Vir-encoded type IV secretion system reveals protein subassemblies[J]. Proceedings of the National Academy of Sciences of the United States of America, 2002, 99(17): 11493-11500.
    [25] ZUPAN J, HACKWORTH CA, AGUILAR J, WARD D, ZAMBRYSKI P. VirB1* promotes T-Pilus formation in the Vir-type IV secretion system of Agrobacterium tumefaciens[J]. Journal of Bacteriology, 2007, 189(18): 6551-6563.
    [26] MARY C, FOUILLEN A, BESSETTE B, NANCI A, BARON C. Interaction via the N terminus of the type IV secretion system (T4SS) protein VirB6 with VirB10 is required for VirB2 and VirB5 incorporation into T-pili and for T4SS function[J]. Journal of Biological Chemistry, 2018, 293(35): 13415-13426.
    [27] WATARAI M, MAKINO SI, SHIRAHATA T. An essential virulence protein of Brucella abortus, VirB4, requires an intact nucleoside-triphosphate-binding domain[J]. Microbiology, 2002, 148(Pt 5): 1439-1446.
    [28] HARE S, BAYLISS R, BARON C, WAKSMAN G. A large domain swap in the VirB11 ATPase of Brucella suis leaves the hexameric assembly intact[J]. Journal of Molecular Biology, 2006, 360(1): 56-66.
    [29] MIRKALANTARI S, ZARNANI AH, NAZARI M, IRAJIAN GR, AMIRMOZAFARI N. Brucella melitensis VirB12 recombinant protein is a potential marker for serodiagnosis of human brucellosis[J]. Annals of Clinical Microbiology and Antimicrobials, 2017, 16(1): 8.
    [30] SMITH EP, MILLER CN, CHILD R, CUNDIFF JA, CELLI J. Postreplication roles of the Brucella VirB type IV secretion system uncovered via conditional expression of the VirB11 ATPase[J]. mBio, 2016, 7(6): e01730-16.
    [31] BORRIELLO G, RUSSO V, PARADISO R, RICCARDI MG, CRISCUOLO D, VERDE G, MARASCO R, PEDONE PV, GALIERO G, BAGLIVO I. Different impacts of MucR binding to the babR and virB promoters on gene expression in Brucella abortus 2308[J]. Biomolecules, 2020, 10(5): 788.
    [32] ALTAMIRANO-SILVA P, MEZA-TORRES J, CASTILLO-ZELEDÓN A, RUIZ-VILLALOBOS N, ZUÑIGA-PEREIRA AM, CHACÓN-DÍAZ C, MORENO E, GUZMÁN-VERRI C, CHAVES-OLARTE E. Brucella abortuA, BOSCHIROLI ML, BOURG G, FOULONGNE V, FRUTOS P, KULAKOV Y, RAMUZ M. A homologue of the Agrobacterium tumefaciens VirB and Bordetella pertussis Ptl type IV secretion systems is essential for intracellular survival of Brucella suis[J]. Molecular Microbiology, 1999, 33(6): 1210-1220.
    [62] STARR T, CHILD R, WEHRLY TD, HANSEN B, HWANG S, LÓPEZ-OTIN C, VIRGIN HW, CELLI J. Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle[J]. Cell Host & Microbe, 2012, 11(1): 33-45.
    [63] VERBEKE J, FAYT Y, MARTIN L, YILMAZ O, SEDZICKI J, REBOUL A, JADOT M, RENARD P, DEHIO C, RENARD HF, LETESSON JJ, de BOLLE X, ARNOULD T. Host cell egress of Brucella abortus requires BNIP3L-mediated mitophagy[J]. EMBO Journal, 2023, 42(14): e112817.
    [64] ZHANG GD, HU H, YIN Y, TIAN MX, BU ZG, DING C, YU SQ. Brucella manipulates host cell ferroptosis to facilitate its intracellular replication and egress in RAW264.7 macrophages[J]. Antioxidants, 2024, 13(5): 577.
    [65] QIU JZ, LUO ZQ. Legionella and Coxiella effectors: strength in diversity and activity[J]. Nature Reviews Microbiology, 2017, 15(10): 591-605.
    [66] BURSTEIN D, AMARO F, ZUSMAN T, LIFSHITZ Z, COHEN O, GILBERT JA, PUPKO T, SHUMAN HA, SEGAL G. Genomic analysis of 38Legionella species identifies large and diverse effector repertoires[J]. Nature Genetics, 2016, 48(2): 167-175.
    [67] ZHANG ZR, FU JQ, RACK JGM, LI C, VOORNEVELD J, FILIPPOV DV, AHEL I, LUO ZQ, DAS C. Legionella metaeffector MavL reverses ubiquitin ADP-ribosylation via a conserved arginine-specific macrodomain[J]. Nature Communications, 2024, 15(1): 2452.
    [68] ESNA ASHARI Z, DASGUPTA N, BRAYTON KA, BROSCHAT SL. An optimal set of features for predicting type IV secretion system effector proteins for a subset of species based on a multi-level feature selection approach[J]. PLoS One, 2018, 13(5): e0197041.
    [69] SHALEM O, SANJANA NE, HARTENIAN E, SHI X, SCOTT DA, MIKKELSON T, HECKL D, EBERT BL, ROOT DE, DOENCH JG, ZHANG F. Genome-scale CRISPR-Cas9 knockout screening in human cells[J]. Science, 2014, 343(6166): 84-87.
    [70] YIN ZW, LI M, NIU C, YU MK, XIE XR, HAI杍瑉獔I 幇鰬氠荇UO WH? SHI吠J, H扅删YY, DING J遂贬洠博癈剁孎杇删硆穂. Des杩內n 襯卦儠杭祵扬奴孩匭塥孰佩譴敯pe vaccine candidate against Brucella type IV secretion system (T4SS)[J]. PLoS One, 2023, 18(8): e0286358.
    [71] WANG YL, WU AD, XU ZY, ZHANG H, LI HH, FU SS, LIU YJ, CUI LJ, MIAO YH, WANG Y, ZHUMANOV K, XU YM, SHENG JL, YI JH, CHEN CF. A multi-epitope subunit vaccine based on CU/ZN-SOD, OMP31 and BP26 against Brucella melitensis infection in BALB/C mice[J]. International Immunopharmacology, 2024, 127: 111351.
    [72] BAI QQ, LI H, WU XL, SHAO JH, SUN MJ, YIN DH. Comparative analysis of the main outer membrane proteins of Brucella in the diagnosis of brucellosis[J]. Biochemical and Biophysical Research Communications, 2021, 560: 126-131.]. Molecular Microbiology, 2008, 70(6): 1378-1396.
    [43] de BARSY M, JAMET A, FILOPON D, NICOLAS C, LALOUX G, RUAL JF, MULLER A, TWIZERE JC, NKENGFAC B, VANDENHAUTE J, HILL DE, SALCEDO SP, GORVEL JP, LETESSON JJ, de BOLLE X. Identification of a Brucella spp. secreted effector specifically interacting with human small GTPase Rab2[J]. Cellular Microbiology, 2011, 13(7): 1044-1058.
    [44] MARCHESINI MI, HERRMANN CK, SALCEDO SP, GORVEL JP, COMERCI DJ. In search of Brucella abortus type IV secretion substrates: screening and identification of four proteins translocated into host cells through VirB system[J]. Cellular Microbiology, 2011, 13(8): 1261-1274.
    [45] SALCEDO SP, MARCHESINI MI, DEGOS C, TERWAGNE M, von BARGEN K, LEPIDI H, HERRMANN CK, SANTOS LACERDA TL, IMBERT PRC, PIERRE P, ALEXOPOULOU L, LETESSON JJ, COMERCI DJ, GORVEL JP. BtpB, a novel Brucella TIR-containing effector protein with immune modulatory functions[J]. Frontiers in Cellular and Infection Microbiology, 2013, 3: 28.
    [46] DÖHMER PH, VALGUARNERA E, CZIBENER C, UGALDE JE. Identification of a type IV secretion substrate of Brucella abortus that participates in the early stages of intracellular survival[J]. Cellular Microbiology, 2014, 16(3): 396-410.
    [47] LOUCHE A, BLANCO A, LACERDA TLS, CANCADE-VEYRE L, LIONNET C, BERGÉ C, ROLANDO M, LEMBO F, BORG JP, BUCHRIESER C, NAGAHAMA M, GÉRARD FCA, GORVEL JP, GUEGUEN-CHAIGNON V, TERRADOT L, SALCEDO SP. Brucella effectors NyxA and NyxB target SENP3 to modulate the subcellular localisation of nucleolar proteins[J]. Nature Communications, 2023, 14(1): 102.
    [48] KAMBAREV S, BORGHESAN E, MILLER CN, MYENI S, CELLI J. The Brucella abortus type IV effector BspA inhibits MARCH6-dependent ERAD to promote intracellular growth[J]. Infection and Immunity, 2023, 91(5): e0013023.
    [49] MILLER CN, SMITH EP, CUNDIFF JA, KNODLER LA, BAILEY BLACKBURN J, LUPASHIN V, CELLI J. A Brucella type IV effector targets the COG tethering complex to remodel host secretory traffic and promote intracellular replication[J]. Cell Host & Microbe, 2017, 22(3): 317-329.e7.
    [50] ZHU JY, DONG Q, DONG CP, ZHANG X, ZHANG H, CHEN ZL. Global lysine crotonylation alterations of host cell proteins caused by Brucella effector BspF[J]. Frontiers in Cellular and Infection Microbiology, 2021, 10: 603457.
    [51] de JONG MF, STARR T, WINTER MG, den HARTIGH AB, CHILD R, KNODLER LA, van DIJL JM, CELLI J, TSOLIS RM. Sensing of bacterial type IV secretion via the unfolded protein response[J]. mBio, 2013, 4(1): e00418-12.
    [52] TSAI AY, BYNDLOSS MX, SEYFFERT N, WINTER MG, YOUNG BM, TSOLIS RM. Tumor necrosis factor alpha contributes to inflammatory pathology in the placenta during Brucella abortus infection[J]. Infection and Immunity, 2022, 90(3): e0001322.
    [53] LIN RQ, LI A, LI YZ, SHEN RT, DU FY, ZHENG M, ZHU JY, CHEN JJ, JIANG PF, ZHANG H, LIU JL, CHEN XY, CHEN ZL. The Brucella effector protein BspF regulates apoptosis through the crotonylation of p53[J]. Microorganisms, 2023, 11(9): 2322.
    [54] ARRIOLA BENITEZ PC, REY SERANTES D, HERRMANN CK, PESCE VIGLIETTI AI, VANZULLI S, GIAMBARTOLOMEI GH, COMERCI DJ, DELPINO MV. The effector protein BPE005 from Brucella abortus induces collagen deposition and matrix metalloproteinase 9 downmodulation via transforming growth factor β1 in hepatic stellate cells[J]. Infection and Immunity, 2015, 84(2): 598-606.
    [55] LI ZQ, WANG SL, HAN JC, SHI CX, XI L, CUI YY, ZHANG H. Expression of cytokine and Apoptosis-Associated genes in mice bone Marrow-Derived Macrophages stimulated with Brucella recombinant type IV secretion effectors[J]. Cytokine, 2024, 182: 156711.
    [56] ARRIOLA BENITEZ PC, PESCE VIGLIETTI AI, HERRMANN CK, DENNIS VA, COMERCI DJ, GIAMBARTOLOMEI GH, DELPINO MV. Brucella abortus promotes a fibrotic phenotype in hepatic stellate cells, with concomitant activation of the autophagy pathway[J]. Infection and Immunity, 2017, 86(1): e00522-17.
    [57] CORONAS-SERNA JM, LOUCHE A, RODRÍGUEZ-ESCUDERO M, ROUSSIN M, IMBERT PRC, RODRÍGUEZ-ESCUDERO I, TERRADOT L, MOLINA M, GORVEL JP, CID VJ, SALCEDO SP. The TIR-domain containing effectors BtpA and BtpB from Brucella abortus impact NAD metabolism[J]. PLoS Pathogens, 2020, 16(4): e1007979.
    [58] ZHANG J, LI M, LI ZQ, SHI JX, ZHANG Y, DENG XM, LIU LB, WANG Z, QI YY, ZHANG H. Deletion of the type IV secretion system effector VceA promotes autophagy and inhibits apoptosis in Brucella-infected human trophoblast cells[J]. Current Microbiology, 2019, 76(4): 510-519.
    [59] ZHI FJ, ZHOU D, BAI FR, LI JM, XIANG CX, ZHANG GD, JIN YP, WANG AH. VceC mediated IRE1 pathway and inhibited CHOP-induced apoptosis to support Brucella replication in goat trophoblast cells[J]. International Journal of Molecular Sciences, 2019, 20(17): 4104.
    [60] MARCHESINI MI, MORRONE SEIJO SM, GUAIMAS FF, COMERCI DJ. A T4SS effector targets host cell Alpha-Enolase contributing to Brucella abortus intracellular lifestyle[J]. Frontiers in Cellular and Infection Microbiology, 2016, 6: 153.
    [61] O’CALLAGHAN D, CAZEVIEILLE C, ALLARDET-SERVENT
    相似文献
    引证文献
    网友评论
    网友评论
    分享到微博
    发 布
引用本文

张孟涛,戴恩慧,孙东杰,赵彦骁,丁家波. 布鲁氏菌Ⅳ型分泌系统效应因子调控宿主细胞功能研究进展[J]. 微生物学通报, 2025, 52(2): 533-544

复制
分享
文章指标
  • 点击次数:44
  • 下载次数: 76
  • HTML阅读次数: 70
  • 引用次数: 0
历史
  • 收稿日期:2024-08-26
  • 录用日期:2024-11-30
  • 在线发布日期: 2025-02-22
  • 出版日期: 2025-02-20
文章二维码