Аннотация
Бруцеллёз, хроническая зоонозная инфекция, остается глобальной проблемой здравоохранения с ярко выраженной эпидемиологической неоднородностью. Несмотря на глобальное распространение, основное бремя болезни ложится на регионы Ближнего Востока, Центральной Азии, Средиземноморья и Африки, где сохраняется стабильно высокий, а в некоторых странах (таких как Иран, Кыргызстан и Азербайджан) – экстремально высокий уровень заболеваемости, превышающий 100 случаев на 100 000 населения в год. Классические оценки ежегодной заболеваемости (~500 000 случаев) считаются существенно заниженными; по современным данным, реальное число новых случаев может достигать 1,6–2,1 миллиона и даже более, что подчеркивает масштаб эпидемиологической недооценки и недостаточность контроля. Основная проблема контроля над инфекцией обусловлена уникальной способностью возбудителя противостоять иммунному ответу, что и определяет его персистенцию и хроническое течение болезни. Широкое распространение и значительный медико-социальный ущерб, связанные с бруцеллёзом, обусловили большой интерес научного сообщества к изучению его иммунопатогенеза. Однако значительная часть полученных данных представлена в контексте фундаментальной науки и требует адаптации для решения прикладных задач эпидемиологов и инфекционистов, работающих в эндемичных очагах.
Настоящий обзор, открывающий цикл статей, предлагает сфокусированный анализ современных данных о критическом начальном этапе инфекции. В центре внимания – стратегии противодействия Brucella ключевым эффекторным клеткам врождённого иммунитета: макрофагам, нейтрофилам и дендритным клеткам. Детальному разбору подвергаются механизмы, с помощью которых патоген нейтрализует их бактерицидный потенциал, формируя основу для персистенции и хронизации. На основании проведенного анализа можно утверждать, что хронизация бруцеллёза представляет собой результат не сбоя иммунного ответа, а его активного и поэтапного перепрограммирования патогеном, инициируемого на уровне врожденного иммунитета. Понимание этих механизмов имеет ключевое значение для разработки новых стратегий диагностики, контроля и профилактики инфекции в условиях ее устойчивой циркуляции.
Annotation
Brucellosis, a chronic zoonotic infection, remains a global public health problem with distinct epidemiological heterogeneity. Despite its worldwide distribution, the main burden of the disease falls on the regions of the Middle East, Central Asia, the Mediterranean, and Africa, where persistently high, and in some countries (such as Iran, Kyrgyzstan, and Azerbaijan), extremely high incidence rates exceeding 100 cases per 100,000 population per year are maintained. Classical estimates of annual incidence (~500,000 cases) are considered significantly underestimated; according to modern data, the actual number of new cases may reach 1.6–2.1 million or even more, highlighting the scale of epidemiological underreporting and insufficient control.
The main difficulty in combating the infection lies in the pathogen’s unique ability to subvert the immune response, which underlies its persistence and the chronic course of the disease. The wide distribution and significant medical and social damage associated with brucellosis have generated considerable interest in the scientific community in studying its immunopathogenesis. However, a significant portion of the obtained data is presented in the context of fundamental science and requires adaptation for solving applied tasks by epidemiologists and infectious disease specialists working in endemic foci.
This review, which inaugurates a series of articles, offers a focused analysis of modern data on the critical initial stage of infection. The analysis centers on Brucella’s strategies to counteract key effector cells of innate immunity: macrophages, neutrophils, and dendritic cells. A detailed examination is devoted to the mechanisms by which the pathogen neutralizes their bactericidal potential, forming the basis for persistence and chronicity. The conducted analysis allows us to assert that the chronicity of brucellosis results not from a failure of the immune response, but from its active and step-by-step reprogramming by the pathogen, initiated at the level of innate immunity. Understanding these mechanisms is crucial for developing new strategies for diagnosis, control, and prevention of the infection under conditions of its sustained circulation.
Key words: brucellosis; Brucella; epidemiology; nnate immunity; macrophages; neutrophils; dendritic cells; pathogenesis; persistence; review
Список литературы
литературы/ References
Celli J. The intracellular life cycle of Brucella spp. Microbiol Spectr. 2019;7(2). 10-1128. doi: 10.1128/microbiolspec.BAI-0006-2019.
Martirosyan A, Moreno E, Gorvel JP. An evolutionary strategy for a stealthy intracellular Brucella pathogen. Immunol Rev. 2011;240(1):211-34. doi: 10.1111/j.1600-065X.2010.00982.x.
Pappas G. The changing Brucella ecology: novel reservoirs, new threats. Int J Antimicrob Agents. 2010; 36; 1: S8-S11. doi: 10.1016/j.ijantimicag.2010.06.013.
Gorvel JP, Moreno E. Brucella intracellular life: from invasion to intracellular replication. Vet Microbiol. 2002; 20; 90(1-4): 281-97. doi: 10.1016/s0378-1135(02)00214-7.
Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV. The new global map of human brucellosis. Lancet Infect Dis. 2006; 6(2): 91-9. doi: 10.1016/S1473-3099(06)70382-6.
Laine CG, Johnson VE, Scott HM, Arenas-Gamboa AM. Global estimate of human brucellosis incidence. Emerg Infect Dis. 2023; 29(9): 1789. doi: 10.3201/eid2909.230052.
Hull NC, Schumaker BA. Comparisons of brucellosis between human and veterinary medicine. Infect Ecol Epidemiol. 2018; 8(1): 1500846. doi: 10.1080/20008686.2018.1500846.
Abdeen A, Ali H, Bardenstein S, Blasco JM, Cardoso R, Corrêa De Sá MI, et al. Brucellosis in the Mediterranean countries: history, prevalence, distribution, current situation and attempts at surveillance and control. AGRIS – International System for Agricultural Science and Technology. 2019; 12(3): 45-58.
Shaqra QMA. Epidemiological aspects of brucellosis in Jordan. Eur J Epidemiol. 2000;16:581-4. doi: 10.1023/A:1007688925027.
Yespembetov BA, Syrym NS, Syzdykov MS, Kuznetsov AN, Koshemetov ZK, Mussayeva AK, et al. Impact of geographical factors on the spread of animal brucellosis in the Republic of Kazakhstan. Comp Immunol Microbiol Infect Dis. 2019; 67: 101349. doi:10.1016/j.cimid.2019.101349.
Ducrotoy M, Bertu WJ, Matope G, Cadmus S, Conde-Álvarez R, Gusi AM, et al. Brucellosis in Sub-Saharan Africa: Current challenges for management, diagnosis and control. Acta Trop. 2017; 165: 179-93. doi: 10.1016/j.actatropica.2015.10.023.
Dadar M, Alamian S, Zowghi E. Comprehensive study on human brucellosis seroprevalence and Brucella species distribution in Iran (1970-2023). Microb Pathog. 2025; 198: 107137. doi: 10.1016/j.micpath.2024.107137.
Bonfoh B, Kasymbekov J, Dürr S, Toktobaev N, Doherr MG, Schueth T, et al. Representative seroprevalences of brucellosis in humans and livestock in Kyrgyzstan. EcoHealth. 2012; 9: 132-8. doi:10.1007/s10393-012-0784-4.
Abdullayev R, Kracalik I, Ismayilova R, Ustun N, Talibzade A, Blackburn JK. Analyzing the spatial and temporal distribution of human brucellosis in Azerbaijan (1995–2009) using spatial and spatio-temporal statistics. BMC Infect Dis. 2012; 12: 1-12. doi:10.1186/1471-2334-12-185. doi: 10.1186/1471-2334-12-185.
Laine CG, Scott HM, Arenas-Gamboa AM. Human brucellosis: Widespread information deficiency hinders an understanding of global disease frequency. PLoS Negl Trop Dis. 2022; 16(5): e0010404. doi:10.1371/journal.pntd.0010404.
Zhang N, Zhou H, Huang DS, Guan P. Brucellosis awareness and knowledge in communities worldwide: a systematic review and meta-analysis of 79 observational studies. PLoS Negl Trop Dis. 2019; 13(5): e0007366. doi:10.1371/journal.pntd.0007366.
Carvalho TFA, Silva ALD, Castanheira TLL, Souza TDD, Paixão TA, Lazaro-Anton L, et al. Cell and tissue tropism of Brucella spp. Infect Immun. 2023; 91(5): e00062-23. doi: 10.1128/iai.00062-23.
Köse Ş, Senger SS, Akkoçlu G, Kuzucu L, Ulu Y, Ersan G, et al. Clinical manifestations, complications, and treatment of brucellosis: evaluation of 72 cases. Turk J Med Sci. 2014; 44(2): 220-3. doi: 10.3906/sag-1112-34.
Dadar M, Fakhri Y, Shahali Y, Khaneghah AM. Contamination of milk and dairy products by Brucella species: A global systematic review and meta-analysis. Food Res Int. 2020; 128: 108775. doi: 10.1016/j.foodres.2019.108775
Korkmaz P, Kartal ED. Skin manifestations associated with brucellosis. EMJ Dermatol. 2016; 4(1): 119-125. doi: 10.33590/emjdermatol/10312753
Pereira CR, Cotrim de Almeida JVF, Cardoso de Oliveira IR, Faria de Oliveira L, Pereira LJ, Zangerônimo MG, et al. Occupational exposure to Brucella spp.: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2020; 14(5): e0008164. doi: 10.1371/journal.pntd.0008164.
Ollé-Goig JE, Canela-Soler J. An outbreak of Brucella melitensis infection by airborne transmission among laboratory workers. Am J Public Health. 1987; 77(3): 335-8. doi: 10.2105/ajph.77.3.335
Huy TXN. Exploring the impact of brucellosis on maternal and child health: transmission mechanisms, patient effects, and current trends in drug use and resistance: a scoping review. Beni-Suef Univ J Basic Appl Sci. 2024; 13(1): 108. doi: 10.1186/s43088-024-00569-8.
Şevik M. Zoonotic abortifacient agents in bovine abortion: diagnostic assessment of 125 cases (2015-2017). Vet Med Sci. 2025; 11(3): e70354. doi: 10.1002/vms3.70354.
Enright FM. The pathogenesis and pathobiology of Brucella infection in domestic animals. In: Nielsen K, Duncan JR, editors. Animal brucellosis. Boca Raton (FL): CRC Press; 1990.
Tuon FF, Gondolfo RB, Cerchiari N. Human-to-human transmission of Brucella – a systematic review. Trop Med Int Health. 2017; 22(5): 539-46. doi: 10.1111/tmi.12856.
Zhang H., Wang Y., Wang Y., Yi J., Deng X., Ma Z., et al. Expression of cytokine and apoptosis-related genes in murine macrophages and dendritic cells stimulated with Brucella melitensis recombinant proteins. Vet Microbiol. 2022; 265: 105-112. doi: 10.21203/rs.3.rs-1151478/v1.
Zheng M, Lin R, Zhu J, Dong Q, Chen J, Jiang P, et al. Effector proteins of type IV secretion system: weapons of Brucella used to fight against host immunity. Curr Stem Cell Res Ther. 2024; 19(2): 145-53. doi: 10.2174/1574888X18666230222124529.
Rivas-Solano O, Van der Henst M, Castillo-Zeledón A, Suárez-Esquivel M, Muñoz-Vargas L, Capitan-Barrios Z, et al. The regulon of Brucella abortus two-component system BvrR/BvrS reveals the coordination of metabolic pathways required for intracellular life. PLoS One. 2022; 17(9): e0274397. doi: 10.1371/journal.pone.0274397
Zhang L, Bai J, Li L, Jia Y, Qiu X, Luo Y, et al. The role of outer membrane protein 16 in Brucella pathogenesis, vaccine development, and diagnostic applications. Vet Sci. 2025; 12(7): 605. doi: 10.3390/vetsci12070605.
Spera JM, Ugalde JE, Mucci J, Comerci DJ, Ugalde RA. A B lymphocyte mitogen is a Brucella abortus virulence factor required for persistent infection. Proc Natl Acad Sci U S A. 2006; 103(44): 16514-9. doi: 10.1073/pnas.0603362103.
Salcedo SP, Marchesini MI, Lelouard H, Fugier E, Jolly G, Balor S, et al. Brucella control of dendritic cell maturation is dependent on the TIR-containing protein Btp1. PLoS Pathog. 2008; 4(2): e21. doi: 10.1371/journal.ppat.0040021.
de Figueiredo P, Ficht TA, Rice-Ficht A, Rossetti CA, Adams LG. Pathogenesis and immunobiology of brucellosis: review of Brucella–Host Interactions. Am J Pathol. 2015; 185(6): 1505-17. doi: 10.1016/j.ajpath.2015.03.003.
Backert S, Meyer TF. Type IV secretion systems and their effectors in bacterial pathogenesis. Curr Opin Microbiol. 2006; 9(2): 207-17. doi: 10.1016/j.mib.2006.02.008.
Ferrero MC, Fossati CA, Rumbo M, Baldi PC. Brucella invasion of human intestinal epithelial cells elicits a weak proinflammatory response but a significant CCL20 secretion. FEMS Immunol Med Microbiol. 2012; 66(1): 45-57. doi: 10.1111/j.1574-695X.2012.00985.x.
Huy TX, Nguyen TT, Kim H, Reyes AW, Kim S. Brucella phagocytosis mediated by pathogen-host interactions and their intracellular survival. Microorganisms. 2022; 10(10): 2003. doi: 10.3390/microorganisms10102003.
Sedzicki J, Tschon T, Low SH, Willemart K, Goldie KN, Letesson JJ, Stahlberg H, Dehio C. 3D correlative electron microscopy reveals continuity of Brucella-containing vacuoles with the endoplasmic reticulum. J Cell Sci. 2018; 131(4): jcs210799. doi: 10.1242/jcs.210799.
Lapaque N, Moriyon I, Moreno E, Gorvel JP. Brucella lipopolysaccharide acts as a virulence factor. Curr Opin Microbiol. 2005; 8(1): 60-6. doi: 10.1016/j.mib.2004.12.003.
Smith JA. Brucella lipopolysaccharide and pathogenicity: the core of the matter. Virulence. 2018; 9(1): 379-382. doi:10.1080/21505594.2017.1395544.
Deniset JF, Kubes P. Recent advances in understanding neutrophils. F1000Res. 2016; 5: 2912. doi:10.12688/f1000research.9691.1.
Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011; 11(8): 519-31. doi:10.1038/nri3024.
Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004; 303(5663): 1532-5. doi: 10.1126/science.1092385.
van Gisbergen KP, Sanchez-Hernandez M, Geijtenbeek TB, van Kooyk Y. Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-1 and DC-SIGN. J Exp Med. 2005; 201(8): 1281-92. doi:10.1084/jem.20041276.
Marshall JS. Mast-cell responses to pathogens. Nat Rev Immunol. 2004; 4(10): 787-99., doi: 10.1038/nri1460.
Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. (2013); 13: 159–75. doi: 10.1038/nri3399.
Hu H, Tian M, Yin Y, Zuo D, Guan X, Ding C, Yu S. Brucella induces heme oxygenase‐1 expression to promote its infection. Transbound Emerg Dis. 2022 Sep; 69(5): 2697-711. doi: 10.1111/tbed.14424
Jiao H, Zhou Z, Li B, Xiao Y, Li M, Zeng H, et al. The mechanism of facultative intracellular parasitism of Brucella. Int J Mol Sci. 2021; 22(7): 3673. doi: 10.3390/ijms22073673.
Zhai Y, Wang H, Zhang G, Li B, Diao Z, Chen L, et al. Transcription factor OxyR regulates peroxidase levels to enhance Brucella’s defense against oxidative stress. Vet Microbiol. 2025;110673. doi: 10.1016/j.vetmic.2025.110673.
Barquero-Calvo E, Mora-Cartín R, Arce-Gorvel V, de Diego JL, Chacón-Díaz C, Chaves-Olarte E, et al. Brucella abortus induces the premature death of human neutrophils through the action of its lipopolysaccharide. PLoS Pathog. 2015; 11(5): e1004853. doi: 10.1371/journal.ppat.1004853.
Gutiérrez-Jiménez C, Mora-Cartín R, Altamirano-Silva P, Chacón-Díaz C, Chaves-Olarte E, Moreno E, et al. Neutrophils as Trojan horse vehicles for Brucella abortus macrophage infection. Front Immunol. 2019; 10: 1012. doi: 10.3389/fimmu.2019.01012.
Barquero-Calvo E, Chaves-Olarte E, Weiss DS, Guzman-Verri C, Chacon-Diaz C, Rucavado A, et al. Brucella abortus uses a stealthy strategy to avoid activation of the innate immune system during the onset of infection. PLoS One. 2007; 2(7): e631. doi: 10.1371/journal.pone.0000631.
de Kleijn S, et al. IFN-γ-stimulated neutrophils suppress lymphocyte proliferation through expression of PD-L1. PLoS One. 2013; 8(8): e72249. doi: 10.1371/journal.pone.0072249.
Barquero-Calvo E, Martirosyan A, Ordoñez-Rueda D, Arce-Gorvel V, Alfaro-Alarcón A, Lepidi H, et al. Neutrophils exert a suppressive effect on Th1 responses to intracellular pathogen Brucella abortus. PLoS Pathog. 2013; 9(2): e1003167. doi: 10.1371/journal.ppat.1003167. doi: 10.1371/journal.ppat.1003167.
Leliefeld PH, Koenderman L, Pillay J. How neutrophils shape adaptive immune responses. Front Immunol. 2015; 6: 471. doi: 10.3389/fimmu.2015.00471.
Zanna MY, Yasmin AR, Omar AR, Arshad SS, Mariatulqabtiah AR, Nur-Fazila SH, et al. Review of dendritic cells, their role in clinical immunology, and distribution in various animal species. Int J Mol Sci. 2021; 28; 22(15): 8044. doi.org/10.3390/ijms22158044
Moll H. Dendritic cells and host resistance to infection. Cell Microbiol. 2003; 5(8): 493-500. doi: 10.1046/j.1462-5822.2003.00291.x.
Oliveira SC, de Oliveira FS, Macedo GC, de Almeida LA, Carvalho NB. The role of innate immune receptors in the control of Brucella abortus infection: toll-like receptors and beyond. Microbes Infect. 2008; 10(9): 1005-9. doi: 10.1016/j.micinf.2008.07.005.
Liu J, Zhang X, Cheng Y, Cao X. Dendritic cell migration in inflammation and immunity. Cell Mol Immunol. 2021; 18(11): 2461-2471. doi: 10.1038/s41423-021-00726-4.
Cabeza-Cabrerizo M, Cardoso A, Minutti CM, Pereira da Costa M, Reis e Sousa C. Dendritic cells revisited. Annu Rev Immunol. 2021; 39: 131-166. doi: 10.1146/annurev-immunol-061020-053707.
Papadopoulos A, Gagnaire A, Degos C, De Chastellier C, Gorvel JP. Brucella discriminates between mouse dendritic cell subsets upon in vitro infection. Virulence. 2016; 7(1): 33-44. doi: 10.1080/21505594.2015.1108516.
Avila-Calderon ED, Flores-Romo L, Sharon W, et al. Dendritic cells and Brucella spp. interaction: the sentinel host and the stealthy pathogen. Folia Microbiol (Praha). 2020; 65(1): 1-16. doi:10.1007/s12223-019-00691-6.
Yang ZJ, Wang BY, Wang TT, Liu F, Guo YX. Functions of dendritic cells and its association with intestinal diseases. Cells. 2021; 10(3): 583. doi: 10.3390/cells10030583.
Salcedo SP, Marchesini MI, Degos C, Terwagne M, Von Bargen K, Lepidi H, et al. BtpB, a novel Brucella TIR-containing effector protein with immune modulatory functions. Front Cell Infect Microbiol. 2013; 3:28. doi.org/10.3389/fcimb.2013.00028
Billard E, Dornand J, Gross A. Brucella suis prevents human dendritic cell maturation and antigen presentation through regulation of tumor necrosis factor alpha secretion. Infect Immun. 2007; 75(10): 4980-9. doi: 10.1128/IAI.00637-07.
Ross E. A., Devitt A., Johnson J. R. Macrophages: the good, the bad, and the gluttony. Front Immunol. 2021; 12:708186. doi: 10.3389/fimmu.2021.708186.
Lafont F, van der Goot FG. Bacterial invasion via lipid rafts. Cell Microbiol. 2005; 7(5): 613-20. doi: 10.1111/j.1462-5822.2005.00515.x.
Boschiroli ML, Ouahrani-Bettache S, Foulongne V, Michaux-Charachon S, Bourg G, Allardet-Servent A, et al. The Brucella suis virB operon is induced intracellularly in macrophages. Proc Natl Acad Sci U S A. 2002; 5; 99(3): 1544-9. doi: 10.1073/pnas.032514299.
Li J, Zhang G, Zhi F, Zhai Y, Zhou D, Chen H, et al. BtpB inhibits innate inflammatory responses in goat alveolar macrophages through the TLR/NF-κB pathway and NLRP3 inflammasome during Brucella infection. Microb Pathog. 2022; 166: 105536. doi: 10.1016/j.micpath.2022.105536.
Guo X, Zeng H, Li M, Xiao Y, Gu G, Song Z, et al. The mechanism of chronic intracellular infection with Brucella spp. Front Cell Infect Microbiol. 2023; 13: 1129172. doi: 10.3389/fcimb.2023.1129172.
Celli J, de Chastellier C, Franchini DM, Pizarro-Cerda J, Moreno E, Gorvel JP. Brucella evades macrophage killing via VirB-dependent sustained interactions with the endoplasmic reticulum. J Exp Med. 2003; 198(4): 545-56. doi: 10.1084/jem.20030088.
Zhao T, Zhang Z, Li Y, Sun Z, Liu L, Deng X, et al. Brucella abortus modulates macrophage polarization and inflammatory response by targeting glutaminases through the NF-κB signaling pathway. Front Immunol. 2023; 14: 1180837. doi: 10.3389/fimmu.2023.1180837.
Wang Y, Xi J, Yi J, Meng C, Zhao X, Sun Z, et al. Brucella induces M1 to M2 polarization of macrophages through STAT6 signaling pathway to promote bacterial intracellular survival. Res Vet Sci. 2022; 145: 91-101. doi: 10.1016/j.rvsc.2022.02.006.
Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2013; 229(2): 176-85. doi: 10.1002/path.4133.