Cover Page

Cite item


Brucellosis is an infectious, especially dangerous zoonotic disease of agricultural and wild animals, from which it is transmitted to humans and characterized by a chronic course with disability of working-age patients. Bacteria of the genus Brucella are facultative intracellular pathogens capable of multiplying and persisting in the host’s immune cells with the development of chronic infection. The host-specific evolutionary mechanisms allow Brucella to hide and manipulate the systems of innate and acquired cellular immunity to achieve intracellular persistence. The review describes the molecular mechanisms that ensure the persistence of the causative agent of brucellosis. The evolution of Brucella species is associated with the adaptation of intracellular preservation and persistence in the formed granulomatous structures. Understanding the molecular mechanisms of Brucella persistence should be considered in programs for its control and elimination, and also allows the development of new effective tools for the prevention and treatment of brucellosis.

About the authors

Yu. K. Kulakov

Gamaleya National Research Centre of Epidemiology and Microbiology

Author for correspondence.
Russian Federation


  1. Anderson T.D., Cheville N.F. Ultrastructural morphometric analysis of Brucella abortus infected trophoblasts in experimental placentitis. Bacterial replication occurs in rough endoplasmic reticulum. Am. J. Pathol. 1986, 124:226-237.
  2. Atluri V.L., Xavier M.N., de Jong M.F. et al. Interactions of the human Pathogenic Brucella Species with Their Hosts. Ann. Rev. Microb. 2011, 65:523-541.
  3. Barquero-Calvo E., Chaves-Olarte E., Weiss D.S. 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:e631.
  4. Barquero-Calvo E., Mora-Cartin R., Arce-Gorvel V. et al. Brucella abortus induces the premature death of human neutrophils through the action of its lipopolysaccharide. PLoS Pathog. 2015, 11:e1004853.
  5. Byndloss M.X., Tsolis R.M. Brucella spp. Virulence Factors and Immunity. Ann. Rev. Anim. Biosci. 2016, 4:111-127.
  6. Byndloss M.X., Tsolis R.M. Chronic Bacterial Pathogens: Mechanisms of persistence. Microbiol Spectr. 2016, 4 (2).
  7. Celli J., de Chastellier C., Franchini D.M. et al. Brucella evades macrophage killing via VirB-dependent sustained interactions with the endoplasmic reticulum. J. Exp. Med. 2003, 198:545-556.
  8. Conde-Alvarez R., Arce-Gorvel V., Iriarte M. et al. The lipopolysaccharide core of Brucella abortus acts as a shield against innate immunity recognition. PLoS Pathog. 2012, 8:e1002675.
  9. Corbel M.J. Brucellosis: an overview. Emerg. Infect. Dis. 1997, 3:213-221.
  10. de Jong M.F., Starr T., Winter M.G. et al. Sensing of bacterial type IV secretion via the unfolded protein response. mBio. 2013, 4:e00418-12.
  11. De Jong M.F., Tsolis R.M. Brucellosis and type IV secretion. Future Microbiol. 2012, 7(1): 47-58.
  12. De Jong M.F., Rolan H.G., Tsolis R.M. Innate immune encounters of the (Type) 4th kind: Brucella. Cell Microbiol. 2010, 12(9): 1195-1202.
  13. Delrue R.M., Martinez-Lorenzo M., Lestrate P et al. Identification of Brucella spp. genes involved in intracellular trafficking. Cell Microbiol. 2001, 3:487-497.
  14. den Hartigh A.B., Rolan H.G., de Jong M.F., Tsolis R.M. VirB3-VirB6 and VirB8-VirB11, but not VirB7, are essential for mediating persistence of Brucella in the reticuloendothelial system. J. Bacteriol. 2008, 190: 4427-4436.
  15. Fernandes D.M., Baldwin C.L. Interleukin-10 downregulates protective immunity to Brucella abortus. Infection and Immunity. 1995, 63:1130-1133.
  16. Gomes M.T., Campos P.C, Oliveira F.S. et al. Critical role ofASC inflammasomes and bacterial type IV secretion system in caspase-1 activation and host innate resistance to Brucella abortus infection. J. Immunol. 2013, 190:3629-3638.
  17. Hoffmann E.M, Houle J.J. Failure of Brucella abortus lipopolysaccharide (LPS) to activate the alternative to activate the alternative pathway of complement. ht. Immunol. Immunopathol. 1983, 5:65-76.
  18. Hong PC., Tsolis R.M., Ficht T.A. Identification of genes required for chronic persistence of Brucella abortus in mice. Infect. Immun. 2000, 68:4102-4107.
  19. Ke Y., Wang Y, Li W, Chen Z. Type IV secretion system of Brucella spp. and its effectors. Front Cell Infect. Microbiol. 2015, 13, 5:72.
  20. Kulakov Y K. Molecular aspects of Brucella persistence. Mol. Gen. MiCTobiol. Virusol. 2016, 1:1-8.
  21. Macedo G.C., Magnani D.M., Carvalho N.B. et al. Central role of MyD88-dependent dendritic cell maturation and proinflammatory cytokine production to control Brucella abortus infection. J. Immunol. 2008;180:1080-1087.
  22. Martirosyan A., Moreno E., Gorvel J.P An evolutionary strategy for a stealthy intracellular Brucella pathogen. Immunological Reviews. 2011, 240:211-234.
  23. Myeni S., Child R., Ng T.W et al. 2013. Brucella modulates secretory trafficking via multiple type IV secretion effector proteins. PLOS Pathog. 9:e1003556.
  24. O’Callaghan D., Cazevieille C., Allardet-Servent A. et al. A homologue of the Agrobacterium tumefaciens VirB and Bordetella pertussis Ptl type IV secretion systems is essential for intracellular survival of Brucella suis. Mol. Microbiol. 1999, 33:1210-1220.
  25. Pappas G., Papadimitriou P, Akritidis N. et al. The new global map of human brucellosis. Lancet Infect Dis. 2006, 6:91-99.
  26. Pizarro-Cerda J., Meresse S., Parton R.G. et al. Brucella abortus transits through the autophagic pathway and replicates in the endoplasmic reticulum of nonprofessional phagocytes. Infect. Immun. 1998, 66:5711-5724.
  27. Rodriguez-Zapata M., Matias M.J., Prieto A. et al. Human brucellosis is characterized by an intense Th1 profile associated with a defective monocyte function. Infect. Immun. 2010, 78:3272-3279.
  28. Rolбn H.G., Tsolis R.M. Inactivation of the type IV secretion system reduces the Th1 polarization of the immune response to Brucella abortus infection. Infect. Immun. 2008, 76:3207-3213.
  29. Rolan H.G., Tsolis R.M. Mice lacking components of adaptive immunity show increased Brucella abortus virB mutant colonization. Infect. Immun. 2007, 75:2965-2973.
  30. Roux C.M., Rolan H.G., Santos R.L. et al. Brucella requires a functional type IV secretion system to elicit innate immune responses in mice. Cell Microbiol. 2007, 9:1851-1869.
  31. Salcedo S.P, Marchesini M.I., Degos C. et al. BtpB, a novel Brucella TIR-containing effector protein with immune modulatory functions. Front. Cell. Infect. Microbiol. 2013,3:28.
  32. Salcedo S.P., Marchesini M.I., Lelouard H. et al. Brucella control of dendritic cell maturation is dependent on the TIR-containing protein Btpl. PLoS Pathog. 2008, 4:e21.
  33. Sengupta D., Koblansky A., Gaines J. et al. Subversion of innate immune responses by Brucella through the targeted degradation of the TLR signaling adapter, MAL. J. Immunol. 2010, 184:956-964.
  34. Spera J. M., Comerci D. J., Ugalde J. E. Brucella alters the immune response in a prpA-dependent manner. Microb. Pathog. 2014, 0: 8-13.
  35. Spera J.M, Ugalde J,E,, Mucci J. et al. A B lymphocyte mitogen is a Brucella abortus virulence factor required for persistent infection. Proc. Natl. Acad. Sci. USA. 2006, 103:16514-16519.
  36. Starr T., Ng T.W, Wehrly T.D. et al. Brucella intracellular replication requires trafficking through the late endosomal/lysosomal compartment. Traffic. 2008, 9:678-694.
  37. Starr T., Child R., Wehrly T.D. et al. Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle. Cell Host Microbe. 2012, 11: 33-45.
  38. Svetic A., Jian YC., Lu P. et al. Brucella abortus induces a novel cytokine gene expression pattern characterized by elevated IL-10 and IFN-y in CD4+ T cells. Int. Immunol. 1993; 5:877-883.
  39. Terwagne M., Ferooz J., Rolan H.G. et al. Innate immune recognition of flagellin limits systemic persistence of Brucella. Cell Microbiol. 2013, 15:942-960.
  40. Vershilova P.A., Chernisheva M.I., Knyazeva E.N. Pathogenesis and immunology of brucellosis. 1974, Moscow, Meditsina.
  41. Wattam A.R., Foster J.T., Mane S.P. et al. Comparative phylogenomics and evolution of the Brucellae reveal a path to virulence. J. Bacteriol. 2014, 196(5): 920-930.
  42. Wolfram J.H, Butaev M.K., Duysheev A. et al. Epidemiology chapter. Vaccine. 2010, 28 Suppl 5:F77-84.
  43. Xavier M.N., Paxro T.A., den Hartigh A.B. et al. Pathogenesis of Brucella spp. The Open Vet. Sci. J. 2010, 4:109-118.
  44. Xavier M.N., Winter M.G., Spees A.M. et al. CD4+ T cell-derived IL-10 promotes Brucella abortus persistence via modulation of macrophage function. PLoS Pathog. 2013, 9: e1003454.
  45. Yang J., Zhao Y., Shao F. Non-canonical activation of inflammatory caspases by cytosolic LPS in innate immunity. Curr. Opin. Immunol. 2015, 32:78-83.
  46. Zhang X., Kimura Y, Fang C. et al. Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood. 2007, 110:228-236.
  47. Zygmunt M.S., Hagius S.D., Walker J.V., Elzer P.H. Identification of Brucella melitensis 16M genes required for bacterial survival in the caprine host. Microbes Infect. 2006, 8:2849-2854.

Copyright (c) 2018 Kulakov Y.K.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС77-75442 от 01.04.2019 г.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies