Russian Journal of Genetics

, Volume 50, Issue 8, pp 775–797 | Cite as

The virulence factors of Mycobacterium tuberculosis: Genetic control, new conceptions

  • A. A. Prozorov
  • I. A. Fedorova
  • O. B. Bekker
  • V. N. Danilenko
Reviews and Theoretical Articles


The problem of Mycobacterium tuberculosis virulence, together with drug resistance, is becoming key for the design of drugs with a new mechanism of action and the production of modern concepts and tuberculosis treatment schemes. The review describes gene complexes and their products, including mycolic acids and global regulatory systems at the level of transcriptional, translational, and post-translational modification, etc. The criteria for selection of virulence/pathogenicity factors that might be used for comparative genomic analysis of strains differing in the degree of virulence were recommended. The experimental approaches and test systems for an adequate estimation of the virulence degree of different strains of M. tuberculosis were analyzed.


Tuberculosis Virulence Factor Mycobacterium Tuberculosis Mycolic Acid Cyclopropane Ring 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Global Tuberculosis Report, Genewa: World Health Organization, 2012.Google Scholar
  2. 2.
    Balabanova, Y., Nikolayevskyy, V., Ignatyeva, O., et al., Survival of civilian and prisoner drug-sensitive, multi- and extensive drug-resistant tuberculosis cohorts prospectively followed in Russia, PLoS One, 2011, vol. 6. e20531PubMedCentralPubMedGoogle Scholar
  3. 3.
    Udwadia, Z.F., MDR, XDR, TDR tuberculosis: ominous progression, Thorax, 2012, vol. 67, pp. 286–288.PubMedGoogle Scholar
  4. 4.
    Homolka, S., Projahn, M., Feuerriegel, S., et al., High resolution discrimination of clinical Mycobacterium tuberculosis complex strains based on single nucleotide polymorphisms, PLoS One, 2012, vol. 7, no. 7. e39855PubMedCentralPubMedGoogle Scholar
  5. 5.
    Brudey, K., Mycobacterium tuberculosis complex genetic diversity: mining the fourth international spoligotyping database (SpolDB4) for classification, population genetics and epidemiology, BMC Microbiol., 2006, vol. 6, no. 6, p. 23.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Mokrousov, I., Russian “Successful” clone B0/W148 of Mycobacterium tuberculosis Beijing genotype: a multiplex PCR assay for rapid detection and global screening, J. Clin. Microbiol., 2012, vol. 50, no. 11, pp. 3757–3759.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Prozorov, A.A. and Danilenko, V.N., Mycobacteria of the tuberculosis complex: genomics, molecular epidemiology, and evolution trends, Usp. Sovrem. Biol., 2011, vol. 13, no. 3, pp. 227–243.Google Scholar
  8. 8.
    Comas, I., Coscola, M., Luo, T., et al., Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans, Nat. Genet., 2013, vol. 45, no. 10, pp. 1176–1182.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Gagneux, S. and Small, P., Global phylogeography of Mycobacterium tuberculosis and implications for tuberculosis product development, Lancet Infect. Dis., 2007, vol. 7, no. 5, pp. 328–337.PubMedGoogle Scholar
  10. 10.
    Manabe, Y. and Bishai, W., Latent Mycobacterium tuberculosis-persisting, patience, and winning by waiting, Nat. Med., 2000, vol. 6, no. 12, pp. 1327–1329.PubMedGoogle Scholar
  11. 11.
    Smith, I., Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence, Clin. Microbiol. Rev., 2003, vol. 16, no. 3, pp. 463–496.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Mishra, A.K., Driessen, N.N., Appelmelk, B.J., et al., Lipoarabinomannan and related glycoconjugates: structure, biogenesis and role in Mycobacterium tuberculosis physiology and host-pathogen interaction, FEMS Microbiol. Rev., 2011, vol. 35, no. 6, pp. 1126–1157.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Leber, J.H., Crimmins, G.T., Raghavan, S., et al., Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen, PLoS Pathogens., 2008, vol. 4, no. 1, pp. 84–95.Google Scholar
  14. 14.
    Court, N., Vasseur, V., Vacher, R., et al., Partial redundancy of the pattern recognition receptors, scavenger receptors, and C-type lectins for the long-term control of Mycobacterium tuberculosis infection, J. Immunol., 2010, vol. 184, no. 12, pp. 7057–7070.PubMedGoogle Scholar
  15. 15.
    Philips, J.A. and Ernst, J.D., Tuberculosis pathogenesis and immunity, Annu. Rev. Pathol., 2011, vol. 7, pp. 353–384.PubMedGoogle Scholar
  16. 16.
    Bafica, A., Scanga, C.A., Feng, C.G., et al., TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis, J. Exp. Med., 2005, vol. 202, no. 12, pp. 1715–1724.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Kleinnijenhuis, J., Oosting, M., Joosten, L.A.B., et al., Innate immune recognition of Mycobacterium tuberculosis, Clin. Dev. Immunol., 2011, vol. 2011. doi 10.1155/2011/405310Google Scholar
  18. 18.
    Ahmad, S., Pathogenesis, immunology, and diagnosis of latent Mycobacterium tuberculosis infection, Clin. Dev. Immunol., 2011, vol. 2011. doi 10.1155/2011/814943Google Scholar
  19. 19.
    Fenhalls, G., Stevens, L., Bezuidenhout, J., et al., Distribution of IFN-γ, IL-4 and TNF-αprotein and CD8 T cells producing IL-12p40 mRNA in human lung tuberculous granulomas, Immunology, 2002, vol. 105, no. 3, pp. 325–335.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Herrera, M.T., Torres, M., Nevels, D., et al., Compartmentalized bronchoalveolar IFN-γ and IL-12 response in human pulmonary tuberculosis, Tuberculosis, 2009, vol. 89, no. 1, pp. 38–47.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Kellar, K.L., Gehrke, J., Weis, S.E., et al., Multiple cytokines are released when blood from patients with tuberculosis is stimulated with Mycobacterium tuberculosis antigens, PLoS One, 2011, vol. 6, no. 11, pp. 1–17.Google Scholar
  22. 22.
    Guler, R., Parihar, S.P., Spohn, G., et al., Blocking IL-1α but not IL-1β increases susceptibility to chronic Mycobacterium tuberculosis infection in mice, Vaccine, 2011, vol. 29, no. 6, pp. 1339–1346.PubMedGoogle Scholar
  23. 23.
    Roach, D.R., Bean, A.G.D., Demangel, C., et al., TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection, J. Immunol., 2002, vol. 168, no. 9, pp. 4620–462.PubMedGoogle Scholar
  24. 24.
    Cooper, A.M., Adams, L.B., Dalton, D.K., et al., IFN-γ and NO in mycobacterial disease: new jobs for old hands, Trends Microbiol., 2002, vol. 10, no. 5, pp. 221–226.PubMedGoogle Scholar
  25. 25.
    Macmicking, J.D., North, R.J., Lacourse, R., et al., Identification of nitric oxide synthase as a protective locus against tuberculosis, Proc. Natl. Acad. Sci. U.S.A., 1997, vol. 94, no. 10, pp. 5243–5248.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Cooper, A.M., Dalton, D.K., Stewart, T.A., et al., Disseminated tuberculosis in interferon gene-disrupted mice, J. Exp. Med., 1993, vol. 178, no. 6, pp. 2243–2247.PubMedGoogle Scholar
  27. 27.
    Saunders, B.M., Frank, A.A., Orme, I.M., et al., Interleukin-6 induces early gamma interferon production in the infected lung but is not required for generation of specific immunity to Mycobacterium tuberculosis infection, Infect. Immun., 2000, vol. 68, no. 6, pp. 3322–3326.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Pompei, L., Jang, S., Zamlynny, B., et al., Disparity in IL-12 release in dendritic cells and macrophages in response to Mycobacterium tuberculosis is due to use of distinct TLRs, J. Immunol., 2007, vol. 178, no. 8, pp. 5192–5199.PubMedGoogle Scholar
  29. 29.
    Filipe-Santos, O., Bustamante, J., Chapgier, A., et al., Inborn errors of IL-12/23- and IFN-γ mediated immunity: molecular, cellular, and clinical features, Semin. Immunol., 2006, vol. 18, no. 6, pp. 347–361.PubMedGoogle Scholar
  30. 30.
    Mayanja-Kizza, H., Wajja, A., Wu, M., et al., Activation of β-chemokines and CCR5 in persons infected with human immunodeficiency virus type 1 and tuberculosis, J. Infect. Dis., 2001, vol. 183, no. 12, pp. 1801–1804.PubMedGoogle Scholar
  31. 31.
    Algood, H.M.S., Chan, J., and Flynn, J.L., Chemokines and tuberculosis, Cytokine Growth Factor Rev., 2003, vol. 14, no. 6, pp. 467–477.PubMedGoogle Scholar
  32. 32.
    Serbina, N.V., Jia, T., Hohl, T.M., et al., Monocytemediated defence against microbial pathogens, Annu. Rev. Immunol., 2008, vol. 26, pp. 421–452.PubMedCentralPubMedGoogle Scholar
  33. 33.
    Takeda, K. and Akira, S., Toll-like receptors in innate immunity, Int. Immunol., 2005, vol. 17, no. 1, pp. 1–14.PubMedGoogle Scholar
  34. 34.
    Fenton, M. and Vermeulen, M., Immunopathology of tuberculosis: role of macrophages and monocytes, Infect. Immun., 1996, vol. 64, no. 3, pp. 683–690.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Glickman, M. and Jacobs, W., Microbial pathogenesis of Mycobacterium tuberculosis: down of a discipline, Cell, 2001, vol. 104, no. 2, pp. 477–485.PubMedGoogle Scholar
  36. 36.
    Esmail, H., Barry, C.E., and Wilkinson, R.J., Understanding latent tuberculosis: the key to improved diagnostic and novel treatment strategies, Drug Discov. Today, 2012, vol. 17, nos. 9–10, pp. 514–521.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Gideon, H.P. and Flynn, J.L., Latent tuberculosis: what the host “sees”?, Immunol. Results, 2011, vol. 50, pp. 202–212.Google Scholar
  38. 38.
    Suhail, A., New approaches in the diagnosis and treatment of latent tuberculosis infection, Respir. Res., 2010, vol. 11, no. 1, p. 169.Google Scholar
  39. 39.
    Shleeva, M.O., Salina, E.G., and Kaprel’yants, A.S., Dormant forms of mycobacteria, Microbiology, 2010, vol. 79, no. 1, pp. 1–12.Google Scholar
  40. 40.
    Keren, I., Minami, S., Rubin, E., and Lewis, K., Characterization and transcriptome analysis of Mycobacterium tuberculosis persisters, MBio, 2011, vol. 2, no. 3. doi 10.1128/mBio.00100-11Google Scholar
  41. 41.
    Lyte, M., The microbial organ in the gut as a driver of homeostasis and disease, Med. Hypotheses, 2010, vol. 74, pp. 634–638.PubMedGoogle Scholar
  42. 42.
    Lyte, M., Microbial Endocrinology: A Personal Journey, 2010. doi 10.1007/978-1-4419-5576-01Google Scholar
  43. 43.
    Lyte, M., Microbial endocrinology and infectious disease in the 21st century, Trends Microbiol., 2004, vol. 12, no. 1, pp. 14–20.PubMedGoogle Scholar
  44. 44.
    Chen, X., Souza, R.D., and Hong, S., The role of gut microbiota in the gut-brain axis: current challenges and perspectives, Protein Cell, 2013, vol. 4, no. 6, pp. 403–414.PubMedGoogle Scholar
  45. 45.
    Norris, V., Molina, F., and Gewirtz, A.T., Hypothesis: bacteria control host appetites, J. Bacteriol., 2013, vol. 195, no. 3, pp. 411–416.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Foster, J.A. and McVey Neufeld, K., Gut-brain axis: how the microbiome influences anxiety and depression, Trends Neirosci., 2013, vol. 36, no. 5, pp. 305–312.Google Scholar
  47. 47.
    Douglas-Escobar, M., Elliott, E., and Neu, J., Effect of intestinal microbial ecology on the developing brain, Jama Pediatr., 2013, vol. 167, no. 4, pp. 374–379.PubMedGoogle Scholar
  48. 48.
    Dinan, T.G. and Quigley, E.M., Probiotics in the treatment of depression: science or science fiction? Aust. N. Z. J. Psychiatry, 2011, vol. 45, pp. 1023–1025.PubMedGoogle Scholar
  49. 49.
    Moloney, R.D., Desbonnet, L., Clarke, G., et al., The microbiome: stress, health and disease, Mamm. Genome, 2014, vol. 25, nos. 1–2, pp. 49–74.PubMedGoogle Scholar
  50. 50.
    Lawn, S.D., Wood, R., and Wilkinson, R.J., Changing concepts of “latent tuberculosis infection” in patients living with HIV infection, Clin. Dev. Immunol., 2011, vol. 2011. 10.1155/2011/980594
  51. 51.
    Salina, T.I. and Morozova, T.I., Molecular genetic analysis of the isoniazid-resistant strains of M. tuberculosis circulating over the Saratov region, Mol. Gen. Microbiol. Virol., 2013, vol. 3, pp. 8–26.Google Scholar
  52. 52.
    Safi, H., Lingaraju, S., and Amin, A., Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-β-D-arabinose biosynthetic and utilization pathway genes, Nat. Genet., 2013, vol. 45, no. 10, pp. 1190–1197.PubMedGoogle Scholar
  53. 53.
    Hickman, S.P., Chan, J., Salgame, P., et al., Mycobacterium tuberculosis induces differential cytokine production from dendritic cells and macrophages with divergent effects on naive T cell polarization, J. Immunol., 2002, vol. 168, no. 9, pp. 4636–4642.PubMedGoogle Scholar
  54. 54.
    Bermudez, L.E. and Goodman, J., Mycobacterium tuberculosis invades and replicates within type II alveolar cells, Infect. Immun., 1996, vol. 64, no. 4, pp. 1400–1406.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Franzblau, S.G., DeGroote, M.A., Cho, S.H., et al., Comprehensive analysis of methods used for the evaluation of compounds against Mycobacterium tuberculosis, Tuberculosis, 2012, vol. 92, no. 6, pp. 453–488.PubMedGoogle Scholar
  56. 56.
    Melo, M.D. and Stokes, R.W., Interaction of Mycobacterium tuberculosis with MH-S, an immortalized murine alveolar macrophage cell line: a comparison with primary murine macrophages, Tubercle Lung Dis., 2000, vol. 80, no. 1, pp. 35–46.Google Scholar
  57. 57.
    Kapina, M.A., Rubakova, E.I., Majorov, K.B., et al., Capacity of lung stroma to educate dendritic cells inhibiting mycobacteria-specific T-cell response depends upon genetic susceptibility to tuberculosis, PLoS One, 2013, vol. 8, no. 8. e72773PubMedCentralPubMedGoogle Scholar
  58. 58.
    Apt, A.S., Are mouse models of human mycobacterial diseases relevant? Genetics says: ‘yes!,’ Immunology, vol. 134, no. 2, pp. 109–115.Google Scholar
  59. 59.
    Kramnik, I., Dietrich, W.F., Demant, P., et al., Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis, Proc. Natl. Acad. Sci. U.S.A., 2000, vol. 97, no. 15, pp. 8560–8568.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Rindi, L., Fattorini, L., Bonanni, D., et al., Involvement of the fadD33 gene in the growth of Mycobacterium tuberculosis in the liver of BALB/c mice, Microbiology, 2002, vol. 148, no. 12, pp. 3873–3880.PubMedGoogle Scholar
  61. 61.
    Shi, L., Jung, Y.J., Tyagi, S., et al., Expression of Th1mediated immunity in mouse lungs induces a Mycobacterium tuberculosis transcription pattern characteristic of nonreplicating persistence, Proc. Natl. Acad. Sci. U.S.A., 2003, vol. 100, no. 1, pp. 241–246.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Poltorak, A., He, X., Smirnova, I., et al., Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene, Science, 1998, vol. 282, no. 5396, pp. 2085–2088.PubMedGoogle Scholar
  63. 63.
    Converse, P.J., Dannenberg, A.M., Estep, J.E., et al., Cavitary tuberculosis produced in rabbits by aerosolized virulent tubercle bacilli, Infect. Immun., 1996, vol. 64, no. 11, pp. 4776–4787.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Ghadimi, D., de Vrese, M., Heller, K.J., et al., Lactic acid bacteria enhance autophagic ability of mononuclear phagocytes by increasing Th1 autophagy-promoting cytokine (IFN-gamma) and nitric oxide (NO) levels and reducing Th2 autophagy-restraining cytokines (IL-4 and IL-13) in response to Mycobacterium tuberculosis antigen, Int. Immunopharmacol., 2010, vol. 10, no. 6, pp. 694–706.PubMedGoogle Scholar
  65. 65.
    Meena, L.S. and Rajni, Survival mechanisms of pathogenic Mycobacterium tuberculosis H37Rv, FEBS J., 2010, vol. 277, no. 11, pp. 2416–2427.PubMedGoogle Scholar
  66. 66.
    Forrelad, M., Klepp, L., Gioffe, A., et al., Virulence factors of the Mycobacterium tuberculosis complex, Virulence, 2013, vol. 4, no. 1, pp. 3–66.Google Scholar
  67. 67.
    Neyrolles, O., Recent advances in deciphering the contribution of Mycobacterium tuberculosis lipids to pathogenesis, Tuberculosis, 2011, vol. 91, no. 3, pp. 187–195.PubMedGoogle Scholar
  68. 68.
    Jankute, M., Grover, Sh., Rana, A., et al., Arabinogalactan and lipoarabinomannan biosynthesis: structure, biogenesis and their potential as drug targets, Future Microbiol., 2012, vol. 7, no. 1, pp. 120–147.Google Scholar
  69. 69.
    Mukherjee, R. and Chattej, D., Glycopeptidolipids: immuno-modulators in grelasy mycobacterial cell envelope, LUBMB Life, 2012, vol. 6, no. 3, pp. 215–225.Google Scholar
  70. 70.
    Lea-Smith, D., Pyke, J., Tull, D., et al., The reductase that catalyzes mycolic motif synthesis is required for efficient attachment of mycolic acid to arabinogalactan, J. Biol. Chem., 2007, vol. 282, no. 15, pp. 11000–11008.PubMedGoogle Scholar
  71. 71.
    George, K., Yuan, Y., Shermans, D., et al., The biosynthesis of cyclopropanatemycolic acids in Mycobacterium tuberculosis, J. Biol. Chem., 1995, vol. 270, no. 45, pp. 27292–27298.PubMedGoogle Scholar
  72. 72.
    Glickman, M., Cording, cord factors, and trehalosedimycolate, The Mycobacterium Cell Envelope, Daffe, M. and Reyrat, J.-M., Eds., Washington, DC: ASM Press, 2008, pp. 63–73.Google Scholar
  73. 73.
    Vander Beken, S., Al Dulayymi, J., Naessens, T., et al., Molecular structure of the Mycobacterium tuberculosis virulence factor, mycolic acid, determines the elicited inflammatory pattern, Eur. J. Immunol., 2011, vol. 41, no. 2, pp. 450–460.Google Scholar
  74. 74.
    Hunter, R., Armitage, L., Jagannath, Ch., et al., TB research at UT-Housten-a review of cord factor: new approaches to drugs, vaccines and the pathogenesis of tuberculosis, Tuberculosis, 2009, vol. 82, no. 1, pp. 18–25.Google Scholar
  75. 75.
    Kochemasova, Z.N., Dykhno, M.M., and Gendon, Yu.Z., Morphological features of microcultures of the tubercle bacilli and acid-tolerant saprophytes, in Voprosy patologii tuberkuleza i izmenchivosti ego vozbuditelya (The Pathology of Tuberculosis and Variability of Its Causative Agent), Strukov, A.I. and Lebedeva, M.N., Eds., Moscow: Medgiz, 1956, pp. 160–165.Google Scholar
  76. 76.
    Prozorov, A.A., The current state of the problem of tubercle bacillus virulence, Sovrem. Probl. Tuberk., 1956, vol. 39, no. 3, pp. 9–17.Google Scholar
  77. 77.
    Noll, H., Bloch, H., Asselinean, J., et al., The chemical structure of the cord factor of Mycobacterium tuberculosis, Biochem. Biophys. Acta, 1956, vol. 20, no. 3, pp. 299–318.PubMedGoogle Scholar
  78. 78.
    Lima, V., Bonato, V., Lima, K., et al., Role of trehalose dimycolate in recruitment of cells and modulation of production of cytokines and in tuberculosis, Infect. Immun., 2001, vol. 69, no. 9, pp. 5305–5312.PubMedCentralPubMedGoogle Scholar
  79. 78a.
    Glickman, M., Cording, cord factors, and trehalosedimycolate, The Mycobacterium Cell Envelope, Daffe, M. and Reyrat, J.-M., Eds., Washington, DC: ASM Press, 2008, pp. 63–73.Google Scholar
  80. 79.
    Dulayymi, J., Baird, M., Maza-Iglesias, M., et al., The first unique synthetic mycobacterial cord factors, Tetrahedron Lett., 2009, vol. 50, no. 19, pp. 3702–3705.Google Scholar
  81. 80.
    Khan, A., Stocter, B., and Timmer, M., Trehalose glycolipids-synthesis and biological activities, Carbohydrate Ros., 2012, vol. 356, no. 1, pp. 25–36.Google Scholar
  82. 81.
    Silva, C., Ekizlerian, S., and Fazioli, R., Role of cord factor in the modulation of infection caused by mycobacteria, Am. J. Pathol., 1958, vol. 118, no. 2, pp. 238–247.Google Scholar
  83. 82.
    Perez, E., Samper, S., Bordas, Y., et al., An essential role for phoP in Mycobacterium tuberculosis virulence, Mol. Microbiol., 2001, vol. 47, no. 1, pp. 179–187.Google Scholar
  84. 83.
    Retzinger, G., Meredith, S., Takayma, K., et al., The role of surface in the biological activities of trehalose6,6-dimycolate: surface properties and development of a model system, J. Biol. Chem., 1981, vol. 256, no. 20, pp. 8208–8216.PubMedGoogle Scholar
  85. 84.
    Schabbing, R., Garcia, A., and Hanter, R., Characterization of the trehalose-6,6-dimycolate surface monolayer by scanning tunneling microscopy, Infect. Immun., 1994, vol. 62, no. 2, pp. 754–756.PubMedCentralPubMedGoogle Scholar
  86. 85.
    Gao, Q., Kripke, K., Arinc, M., et al., Comparative expression studies of a complex phenotype: cord formation in Mycobacterium tuberculosis, Tuberculosis, 2004, vol. 84, no. 3, pp. 188–196.PubMedGoogle Scholar
  87. 86.
    Makinoshima, H. and Glickman, M., Regulation of Mycobacterium tuberculosis cell envelope composition and virulence by intramembrane proteolysis, Nature, 2005, vol. 436, no. 7049, pp. 406–409.PubMedCentralPubMedGoogle Scholar
  88. 87.
    Rao, V., Fujiwara, N., Porcelli, S., et al., Mycobacterium tuberculosis control host innate immune activation through cyclopropane modulation of a glycolipid effector molecule, JEM, 2005, vol. 201, no. 4, pp. 535–543.Google Scholar
  89. 88.
    Onwueme, K., Vos, C., Zurita, J., et al., The dimycocerosate ester polyketide virulence factors of Mycobacterium, Prog. Lipid Res., 2005, vol. 44, no. 2, pp. 259–302.PubMedGoogle Scholar
  90. 89.
    Barkan, D., Rao, V., Sukenick, G., et al., Redundant function of cmaA2 and mmA2 in Mycobacterium tuberculosis cyclopropanation of oxygenated mycolates, J. Bacteriol., 2010, vol. 192, no. 14, pp. 3661–3668.PubMedCentralPubMedGoogle Scholar
  91. 90.
    Gao, L.-Y., Laval, F., Lawson, E., et al., Requirement for kas in Mycobacterium mycolic acid biosynthesis, cell wall impermeability and intracellular survival; implications for therapy, Mol. Microbiol., 2003, vol. 49, no. 6, pp. 1547–1563.PubMedGoogle Scholar
  92. 91.
    Bhatt, A., Fujiwara, N., Bhatt, K., et al., Deletion of kas in Mycobacterium tuberculosis causes loss of acidfastness and subclinical latent tuberculosis in immunocompetent mice, Proc. Natl. Acad. Sci. U.S.A., 2007, vol. 104, no. 12, pp. 5157–5162.PubMedCentralPubMedGoogle Scholar
  93. 92.
    Glickman, M., Cahill, S., and Jacobs, W., The Mycobacterium tuberculosis cmaA2 gene encodes a mycolic acid trans-cyclopropanesynthetase, J. Biol. Chem., 2001, vol. 276, no. 3, pp. 2228–2233.PubMedGoogle Scholar
  94. 93.
    Dao, D., Sweenly, K., Hsu, T., et al., Mycolic acid modification by the mmaA4 gene of Mycobacterium tuberculosis modulates IL-12 production, PLoS Pathogens, 2008, vol. 4, no. 6, pp. 1–14.Google Scholar
  95. 94.
    Yuan, Y., Zhu, Y., Crane, D., et al., The effect of oxygenated mycolic acid composition on cell wall function and macrophage growth in Mycobacterium tuberculosis, Mol. Microbiol., 1998, vol. 29, no. 6, pp. 1449–1458.PubMedGoogle Scholar
  96. 95.
    Behr, M., Schroeder, B., Brinkman, J., et al., A point mutation in the mma3 gene is responsible for impaired methoxymycolic acid production in Mycobacterium bovis BC6 strains obtained offer 1927, J. Bacteriol., 2000, vol. 182, no. 12, pp. 3392–3394.Google Scholar
  97. 96.
    Armitage, L., Jagannath, C., Wanger, A., et al., Disruption of the genes encoding antigen 85A and antigen 85B of Mycobacterium tuberculosis H37Rv: effect on growth in culture and in macrophages, Infect. Immun., 2000, vol. 68, no. 2, pp. 767–778.Google Scholar
  98. 97.
    Mompon, B., Fedenci, C., Toubiana, R., et al., Isolation and structural determination of a cord factor (trehalose-6,6-dimycolate) from Mycobacterium smegmatis, Chem. Phys. Lipids, 1978, vol. 21, nos. 1–2, pp. 97–101.PubMedGoogle Scholar
  99. 98.
    Alibaud, L., Alahari, A., Trivelli, X., et al., Temperature-dependent regulation of mycolic acid cyclopropanation in saprophytic mycobacteria: role of the Mycobacterium smegmatis 1351 gene (MSMEG 1351) cis-cyclopropanation of α-mycolates, J. Biol. Chem., 2010, vol. 285, no. 28, pp. 21698–21707.PubMedCentralPubMedGoogle Scholar
  100. 99.
    Retzinger, G., Dissemination of beads coated with trehalose-6,6-dimycolate a possible role for coagulation in the dissemination process, Exp. Mol. Pathol., 1987, vol. 46, no. 2, pp. 190–198.PubMedGoogle Scholar
  101. 100.
    Glickman, M., Cox, J., and Jacobs, W., A novel mycolic acid cyclopropane synthetase is required for cording, persistence and virulence of Mycobacterium tuberculosis, Mol. Cell, 2000, vol. 5, no. 4, pp. 717–727.PubMedGoogle Scholar
  102. 101.
    Prozorov, A.A., Zaichikova, M.V., and Danilenko, V.N., Mycobacterium tuberculosis mutants with multidrug resistance: history of origin, genetic and molecular mechanisms of resistance, and emerging challenges, Russ. J. Genet., 2013, vol. 49, no. 1, pp. 125–141.Google Scholar
  103. 102.
    Gordon, S., Brosch, R., Billaut, A., et al., Identification of variable regions in the genomes of virulence bacilli using bacterial artificial chromosome arrays, Mol. Microbiol., 1999, vol. 32, no. 3, pp. 643–655.PubMedGoogle Scholar
  104. 103.
    Abdallah, A., Gey van Pittins, N., Champion, P., et al., Type VII secretion-mycobacteria show the way, Nat. Rev. Microbiol., 2007, vol. 5, no. 11, pp. 883–891.PubMedGoogle Scholar
  105. 104.
    Champion, P. and Cox, I.S., Protein secretion system in mycobacteria, Cell Microbiol., 2007, vol. 9, no. 6, pp. 1376–1384.PubMedGoogle Scholar
  106. 105.
    Camacho, L., Ensergueix, D., Perez, E., et al., Identification of a virulence gene clusters of Mycobacterium tuberculosis by signature-target transposon mutagenesis, Mol. Microbiol., 1999, vol. 34, no. 2, pp. 257–267.PubMedGoogle Scholar
  107. 106.
    Mucherjee, R. and Chattej, D., Glycopeptidolipids: immunomodulators in greasy mycobacterial cell envelope, UMB Life, 2012, vol. 6, no. 3, pp. 215–225.Google Scholar
  108. 107.
    Barkan, D., Hedhli, D., Yan, H.-G., et al., Mycobacterium tuberculosis backing all mycolic acid cyclopropanation in viable but high by attenuated and hyperinflammatory in mice, Infect. Immun., 2012, vol. 80, no. 6, pp. 1958–1968.PubMedCentralPubMedGoogle Scholar
  109. 108.
    Tsenova, L., Ellison, E., Harbacheuski, R., et al., Virulence of selected Mycobacterium tuberculosis clinical isolates in the rabbit model of meningitis is dependent on phenolic glycolipid produced by the bacilli, J. Infect. Dis., 2005, vol. 192, no. 1, pp. 98–106.PubMedGoogle Scholar
  110. 109.
    Steyn, A.J., Collins, D.M., Hondalus, M.K., et al., Mycobacterium tuberculosis WhiB3 interacts with RpoV to affect host survival but is dispensable for in vivo growth, Proc. Natl. Acad. Sci. U.S.A., 2002, vol. 99, pp. 3147–3152.PubMedCentralPubMedGoogle Scholar
  111. 110.
    Casonato, S., Sanchez, A.C., Haruki, H., et al., WhiB5, a transcriptional regulator that contributes to Mycobacterium tuberculosis virulence and reactivation, Infect. Immun., 2012, vol. 80, pp. 3132–3134.PubMedCentralPubMedGoogle Scholar
  112. 111.
    Stapleton, M.R., Smith, L.J., Hunt, D.M., et al., Mycobacterium tuberculosis WhiB1 represses transcription of the essential chaperonin GroEL2, Tuberculosis, 2012, vol. 92, no. 4, pp. 328–332.PubMedCentralPubMedGoogle Scholar
  113. 112.
    Konar, M., Alam, Md.S., Arora, C., and Agrawal, P., WhiB2/Rv3260c, a cell division-associated protein of Mycobacterium tuberculosis H37Rv, has properties of a chaperone, FEBS J., 2012, vol. 279, pp. 2781–2792.PubMedGoogle Scholar
  114. 113.
    Chawla, M. and Parikh, P., Mycobacterium tuberculosis WhiB4 regulates oxidative stress response to modulate survival and dissemination in vivo, Mol. Microbiol., 2012, vol. 85, no. 6, pp. 1148–1165.PubMedCentralPubMedGoogle Scholar
  115. 114.
    Alam, Md.S., Garg, S.K., and Agrawal, P., Studies on structural and functional divergence among seven WhiB proteins of Mycobacterium tuberculosis H37Rv, FEBS J., 2009, vol. 276, pp. 76–93.PubMedGoogle Scholar
  116. 115.
    Burian, J., Ramón-García, S., Howes, C.G., and Thompson, C.J., WhiB7, a transcriptional activator that coordinates physiology with intrinsic drug resistance in Mycobacterium tuberculosis, Expert Rev. Anti-Infect. Ther., 2012, vol. 10, no. 9, pp. 1037–1047.PubMedGoogle Scholar
  117. 116.
    McKenzie, J.L., Robson, J., Berney, M., et al., A VapBC toxin-antitoxin module is a posttranscriptional regulator of metabolic flux in mycobacteria, J. Bacteriol., 2012, vol. 194, no. 9, pp. 2189–2204.PubMedCentralPubMedGoogle Scholar
  118. 117.
    Ramage, H.R., Connolly, L.E., and Cox J.S., Comprehensive functional analysis of Mycobacterium tuberculosis toxin-antitoxin systems: implications for pathogenesis, stress responses, and evolution, PLoS Genet., 2009, vol. 5, no. 12, pp. 1–14.Google Scholar
  119. 118.
    Mehra, S., Functional genomics reveals extended roles of the Mycobacterium tuberculosis stress response factor σH, J. Bacteriol., 2009, vol. 191, no. 12, pp. 3965–3980.PubMedCentralPubMedGoogle Scholar
  120. 119.
    Schnappinger, D., Ehrt, S., Voskuil, M.I., et al., Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment, J. Exp. Med., 2003, vol. 198, no. 5, pp. 693–704.PubMedCentralPubMedGoogle Scholar
  121. 120.
    Fisher, M.A., Plikaytis, B.B., and Shinnick, T.M., Microarray analysis of the Mycobacterium tuberculosis transcriptional response to the acidic conditions found in phagosomes, J. Bacteriol., 2002, vol. 184, no. 14, pp. 4025–4032.PubMedCentralPubMedGoogle Scholar
  122. 121.
    Stewart, G.R., Patel, J., Robertson, B.D., et al., Mycobacterial mutants with defective control of phagosomal acidification, PLoS Pathog., 2005, vol. 1, no. 3, pp. 269–278.PubMedGoogle Scholar
  123. 122.
    Shur, K., Maslov, D., Bekker, O., et al., WhiB7 gene polymorphism and its regulon genes in Mycobacterium tuberculosis, as a new mechanism of drug resistance, FEBS J., 2013, vol. 280,suppl. 1, p. 366.Google Scholar
  124. 123.
    Be, N.A., Bishai, W.R., and Jain, S.K., Role of Mycobacterium tuberculosis pknD in the pathogenesis of central nervous system tuberculosis, BMC Microbiol., 2012, vol. 12, no. 7. PMID:22243650Google Scholar
  125. 124.
    Jayakumar, D., Jacobs, W.R., and Narayanan, S., Protein kinase E of Mycobacterium tuberculosis has a role in the nitric oxide stress response and apoptosis in a human macrophage model of infection, Cell Microbiol., 2008, vol. 10, pp. 365–374.PubMedGoogle Scholar
  126. 125.
    Cowley, S., Ko, M., Pick, N., et al., The Mycobacterium tuberculosis protein serine/threonine kinase PknG is linked to cellular glutamate/glutamine levels and is important for growth in vivo, Mol. Microbiol., 2004, vol. 52, pp. 1691–1702.PubMedGoogle Scholar
  127. 126.
    Walburger, A., Koul, A., Ferrari, G., et al., Protein kinase G from pathogenic mycobacteria promotes survival within macrophages, Science, 2004, vol. 304, no. 5678, pp. 1800–1804.PubMedGoogle Scholar
  128. 127.
    McLaughlin, B., Chon, J.S., MacGurn, J.A., et al., A mycobacterium ESX-1-secreted virulence factor with unique requirements for export, PLoS Pathog., 2007, vol. 3, no. 8. e105PubMedCentralPubMedGoogle Scholar
  129. 128.
    Li, A.H., Waddell, S.J., Hinds, J., et al., Contrasting transcriptional responses of a virulent and an attenuated strain of Mycobacterium tuberculosis infecting macrophages, PLoS One, 2010, vol. 5, no. 6. e11066PubMedCentralPubMedGoogle Scholar
  130. 129.
    Fortune, S.M., Jaeger, A., Sarracino, D.A., et al., Mutually dependent secretion of proteins required for mycobacterial virulence, Proc. Natl. Acad. Sci. U.S.A., 2005, vol. 102, pp. 10676–10681.PubMedCentralPubMedGoogle Scholar
  131. 130.
    Bottai, D., Majlessi, L., Simeone, R., et al., ESAT-6 secretion-independent impact of ESX-1 genes espF and espG1 on virulence of Mycobacterium tuberculosis, J. Infect. Dis., 2011, vol. 203, pp. 1155–1164.PubMedGoogle Scholar
  132. 131.
    Brodin, P., Majlessi, L., Marsollier, L., et al., Dissection of ESAT-6 system 1 of Mycobacterium tuberculosis and impact on immunogenicity and virulence, Infect. Immun., 2006, vol. 74, no. 1, pp. 88–98.PubMedCentralPubMedGoogle Scholar
  133. 132.
    Stanley, S.A., Raghavan, S., Hwang, W.W., and Cox, J.S., Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system, Proc. Natl. Acad. Sci. U.S.A., 2003, vol. 100, no. 22, pp. 13001–13006.PubMedCentralPubMedGoogle Scholar
  134. 133.
    Bottai, D. and Brosch, R., Mycobacterial PE, PPE and ESX clusters: novel insights into the secretion of these most unusual protein families, Mol. Microbiol., 2009, vol. 73, pp. 325–328.PubMedGoogle Scholar
  135. 134.
    Wards, B.J., de Lisle, G.W., and Collins, D.M., An esat6 knockout mutant of Mycobacterium bovis produced by homologous recombination will contribute to the development of a live tuberculosis vaccine, Tuber. Lung Dis., 2000, vol. 80, pp. 185–189.PubMedGoogle Scholar
  136. 135.
    Tan, T., Lee, W.L., Alexander, D.C., et al., The ESAT6/CFP-10 secretion system of Mycobacterium marinum modulates phagosome maturation, Cell Microbiol., 2006, vol. 8, no. 9, pp. 1417–1429.PubMedGoogle Scholar
  137. 136.
    Coros, A., Callahan, B., Battaglioli, E., and Derbyshire, K.M., The specialized secretory apparatus ESX-1 is essential for DNA transfer in Mycobacterium smegmatis, Mol. Microbiol., 2008, vol. 69, no. 4, pp. 794–808.PubMedCentralPubMedGoogle Scholar
  138. 137.
    Guinn, K.M., Hickey, M.J., Mathur, S.K., et al., Individual RD1-region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis, Mol. Microbiol., 2004, vol. 51, pp. 359–370.PubMedCentralPubMedGoogle Scholar
  139. 138.
    Sander, P., Rezwan, M., Walker, B., et al., Lipoprotein processing is required for virulence of Mycobacterium tuberculosis, Mol. Microbiol., 2004, vol. 52, pp. 1543–1552.PubMedGoogle Scholar
  140. 139.
    Rampini, S.K., Selchow, P., Keller, C., et al., LspA inactivation in Mycobacterium tuberculosis results in attenuation without affecting phagosome maturation arrest, Microbiology, 2008, vol. 154, pp. 2991–3001.PubMedGoogle Scholar
  141. 140.
    Brzostek, A., Dziadek, B., Rumijowska-Galewicz, A., et al., Cholesterol oxidase is required for virulence of Mycobacterium tuberculosis, FEMS Microbiol. Letts., 2007, vol. 275, pp. 106–112.Google Scholar
  142. 141.
    Copenhaver, R.H., Sepulveda, E., Armitage, L.Y., et al., A mutant of Mycobacterium tuberculosis H37Rv that lacks expression of antigen 85A is attenuated in mice but retains vaccinogenic potential, Infect. Immun., 2004, vol. 72, no. 12, pp. 7084–7095.PubMedCentralPubMedGoogle Scholar
  143. 142.
    Wong, D., Bach, H., Sun, J., et al., Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H+-ATPase to inhibit phagosome acidification, Proc. Natl. Acad. Sci. U.S.A., 2011, vol. 108, pp. 19371–19376.PubMedCentralPubMedGoogle Scholar
  144. 143.
    Iantomasi, R., Sali, M., Cascioferro, A., et al., PE-PGRS30 is required for the full virulence of Mycobacterium tuberculosis, Cell Microbiol., 2012, vol. 14, pp. 356–367.PubMedGoogle Scholar
  145. 144.
    Mohamedmohaideen, N.N., Palaninathan, S.K., Morin, P.M., et al., Structure and function of the virulence-associated high-temperature requirement a of Mycobacterium tuberculosis, Biochemistry, 2008, vol. 47, pp. 6092–6102.PubMedGoogle Scholar
  146. 145.
    Blumenthal, A., Trujillo, C., Ehrt, S., and Schnappinger, D., Simultaneous analysis of multiple Mycobacterium tuberculosis knockdown mutants in vitro and in vivo, PLoS One, 2010, vol. 5, no. 12. e15667PubMedCentralPubMedGoogle Scholar
  147. 146.
    Pearce, M.J., Arora, P., Festa, R.A., et al., Identification of substrates of the Mycobacterium tuberculosis proteasome, EMBO J., 2006, vol. 25, no. 22, pp. 5423–5432.PubMedCentralPubMedGoogle Scholar
  148. 147.
    Lamichhane, G., Raghunand, T.R., Morrison, N.E., et al., Deletion of a Mycobacterium tuberculosis proteasomal ATPase homologue gene produces a slow-growing strain that persists in host tissues, J. Infect. Dis., 2006, vol. 194, pp. 1233–1240.PubMedGoogle Scholar
  149. 148.
    Li, A.H., Waddell, S.J., Hinds, J., et al., Contrasting transcriptional responses of a virulent and an attenuated strain of Mycobacterium tuberculosis infecting macrophages, PLoS One, 2010, vol. 5, no. 6. e11066. doi 10.1371/joumal.pone.0011066PubMedCentralPubMedGoogle Scholar
  150. 149.
    Singh, R., Singh, A., and Tyagi, A.K., Deciphering the genes involved in pathogenesis of Mycobacterium tuberculosis, Tuberculosis, 2005, vol. 85, pp. 325–335.PubMedGoogle Scholar
  151. 150.
    Sassetti, Ch. and Rubin, E., Genetic requirements for mycobacterial survival during infection, Proc. Natl. Acad. Sci. U.S.A., 2003, vol. 100, no. 22, pp. 12989–12994.PubMedCentralPubMedGoogle Scholar
  152. 151.
    Geiman, D., Raghunand, T., Agarwell, N., et al., Differential gene expression in response to exposure to antimycobacterial agents and other stress conditions among seven Mycobacterium tuberculosis Whi B-like genes, Antimicrob. Agentschemother., 2006, vol. 50, no. 8, pp. 2836–2841.Google Scholar
  153. 152.
    Rohde, K., Abramovitch, R., and Russel, D., Mycobacterium tuberculosis invasion of macrophages linking bacterial gene expression to environmental cues, Cell Host Microbe, 2007, vol. 2, no. 15, pp. 352–364.PubMedGoogle Scholar
  154. 153.
    Leplae, R., Geeraerts, D., Hallez, R., et al., Diversity of bacterial type II toxin-antitoxin systems: a comprehensive search and functional analysis of novel families, Nucleic Acids Res., 2011, vol. 39, no. 13, pp. 5513–5525.PubMedCentralPubMedGoogle Scholar
  155. 154.
    Unterholzner, S.J. and Poppenberger Rozhon, W., Toxin-antitoxin systems: biology, identification, and application, Mob. Genet. Elem., 2013, vol. 3, no. 5. e26219Google Scholar
  156. 155.
    Park, S.J., Son, W.S., and Lee, B.J., Structural overview of toxin-antitoxin systems in infectious bacteria: a target for developing antimicrobial agents, Biochim. Biophys. Acta, 2013, vol. 1834, no. 6, pp. 1155–1167.PubMedGoogle Scholar
  157. 156.
    Mehra, S. and Kaushal, D., Functional genomics reveals extended roles of the Mycobacterium tuberculosis stress response factor sigmaH, Bacteriology, 2009, vol. 191, no. 12, pp. 3965–3980.Google Scholar
  158. 157.
    Beste, D.J., Espasa, M., Bonde, B., et al., The genetic requirements for fast and slow growth in mycobacteria, PLoS One, 2009, vol. 4, no. 4. e5349PubMedCentralPubMedGoogle Scholar
  159. 158.
    Arcus, V.L., The PIN-domain toxin-antitoxin array in mycobacteria, Trends Microbiol., 2005, vol. 13, pp. 360–365.PubMedGoogle Scholar
  160. 159.
    Alekseeva, M.G., Danilenko, V.N., Zaichikova, M.V., and Zakharevich, N.V., RF Patent Application no. 2013155216, 2013.Google Scholar
  161. 160.
    Danilenko, V.N., Osolodkin, D.I., and Lakatosh, S.A., Bacterial eukaryotic type serine-threonine protein kinases: tools for targeted anti-infective drug design, Curr. Top. Med. Chem., 2011, vol. 11, no. 10, pp. 1352–1369.PubMedGoogle Scholar
  162. 161.
    Beresford, N.G., Mulhearn, D., Szczepankiewicz, B., et al., Inhibition of MptpB phosphatase from Mycobacterium tuberculosis impairs mycobacterial survival in macrophages, J. Antimicrob. Chemother., 2009, vol. 63, no. 5, pp. 928–936.PubMedGoogle Scholar
  163. 162.
    Teng, T.S., Wang, H.H., and Xie, J.P., Advances in the study of Mycobacterium tuberculosis protein phosphatase and its inhibitors, Yao Xue Xue Bao, 2011, vol. 46, no. 12, pp. 1420–1428.PubMedGoogle Scholar
  164. 163.
    Ventura, M., Canchaya, C., and Tauch, A., Genomics of Actinobacteria: tracing the evolutionary history of an ancient phylum, Microbiol. Mol. Biol. Rev., 2007, vol. 71, no. 3, pp. 495–548.PubMedCentralPubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2014

Authors and Affiliations

  • A. A. Prozorov
    • 1
  • I. A. Fedorova
    • 1
  • O. B. Bekker
    • 1
  • V. N. Danilenko
    • 1
  1. 1.Vavilov Institute of General GeneticsRussian Academy of SciencesMoscowRussia

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