Advertisement

Evolution and Strain Variation in BCG

  • Abdallah M. Abdallah
  • Marcel A. Behr
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1019)

Abstract

BCG vaccines were derived by in vitro passage, during the years 1908–1921, at the Pasteur Institute of Lille. Following the distribution of stocks of BCG to vaccine production laboratories around the world, it was only a few decades before different BCG producers recognized that there were variants of BCG, likely due to different passaging conditions in the different laboratories. This ultimately led to the lyophilization of stable BCG products in the 1950s and 1960s, but not before considerable evolution of the different BCG strains had taken place. The application of contemporary research methodologies has now revealed genomic, transcriptomic and proteomic differences between BCG strains. These molecular differences in part account for phenotypic differences in vitro between BCG strains, such as their variable secretion of antigenic proteins. Yet, the relevance of BCG variability for immunization policy remains elusive. In this chapter we present an overview of what is known about BCG evolution and its resulting strain variability, and provide some speculation as to the potential relevance for a vaccine given to over 100 million newborns each year.

Keywords

Tuberculosis BCG Vaccine Protection Strain 

References

  1. Abdallah AM, Gey Van pittius NC, Champion PA, Cox J, Luirink J, Vandenbroucke-Grauls CM, Appelmelk BJ, Bitter W (2007) Type VII secretion – mycobacteria show the way. Nat Rev Microbiol 5:883–891CrossRefPubMedGoogle Scholar
  2. Abdallah AM, Savage ND, Van zon M, Wilson L, Vandenbroucke-Grauls CM, Van Der Wel NN, Ottenhoff TH, Bitter W (2008) The ESX-5 secretion system of Mycobacterium marinum modulates the macrophage response. J Immunol 181:7166–7175CrossRefPubMedGoogle Scholar
  3. Abdallah AM, Hill-Cawthorne GA, Otto TD, Coll F, Guerra-Assuncao JA, Gao G, Naeem R, Ansari H, Malas TB, ADROUB SA, Verboom T, Ummels R, Zhang H, Panigrahi AK, Mcnerney R, Brosch R, Clark TG, Behr MA, Bitter W, Pain A (2015) Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations. Sci Rep 5: 15443CrossRefPubMedPubMedCentralGoogle Scholar
  4. Alexander DC, Behr MA (2007) Rv1773 is a transcriptional repressor deleted from BCG-Pasteur. Tuberculosis (Edinb) 87:421–425CrossRefGoogle Scholar
  5. Arend SM, Van Soolingen D (2011) Editor’s choice: editorial commentary: low level INH-resistant BCG: a sheep in wolf’s clothing? Clin Infect Dis 52:89–93CrossRefPubMedGoogle Scholar
  6. Aronson JD, Aronson CF, Taylor HC (1958) A twenty-year appraisal of BCG vaccination in the control of tuberculosis. AMA Arch Intern Med 101:881–893CrossRefPubMedGoogle Scholar
  7. Ates LS, Ummels R, Commandeur S, Van de Weerd R, Sparrius M, Weerdenburg E, Alber M, Kalscheuer R, Piersma SR, Abdallah AM, Abd el Ghany M, Abdel-Haleem AM, Pain A, Jimenez CR, Bitter W, Houben EN (2015) Essential role of the ESX-5 secretion system in outer membrane permeability of pathogenic mycobacteria. PLoS Genet 11:e1005190CrossRefPubMedPubMedCentralGoogle Scholar
  8. Azad AK, Sirakova TD, Fernandes ND, Kolattukudy PE (1997) Gene knockout reveals a novel gene cluster for the synthesis of a class of cell wall lipids unique to pathogenic mycobacteria. J Biol Chem 272:16741–16745CrossRefPubMedGoogle Scholar
  9. Bai G, Gazdik MA, Schaak DD, Mcdonough KA (2007) The Mycobacterium bovis BCG cyclic AMP receptor-like protein is a functional DNA binding protein in vitro and in vivo, but its activity differs from that of its M. tuberculosis ortholog, Rv3676. Infect Immun 75:5509–5517CrossRefPubMedPubMedCentralGoogle Scholar
  10. Behr MA (2002) BCG – different strains, different vaccines? Lancet Infect Dis 2:86–92CrossRefPubMedGoogle Scholar
  11. Behr MA, Sherman DR (2007) Mycobacterial virulence and specialized secretion: same story, different ending. Nat Med 13:286–287CrossRefPubMedGoogle Scholar
  12. Behr MA, Small PM (1999) A historical and molecular phylogeny of BCG strains. Vaccine 17:915–922CrossRefPubMedGoogle Scholar
  13. Behr MA, Wilson MA, Gill WP, Salamon H, Schoolnik GK, Rane S, Small PM (1999) Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 284:1520–1523CrossRefPubMedGoogle Scholar
  14. Behr MA, Schroeder BG, Brinkman JN, Slayden RA, Barry CE 3rd (2000) A point mutation in the mma3 gene is responsible for impaired methoxymycolic acid production in Mycobacterium bovis BCG strains obtained after 1927. J Bacteriol 182:3394–3399CrossRefPubMedPubMedCentralGoogle Scholar
  15. Belley A, Alexander D, Di Pietrantonio T, Girard M, Jones J, Schurr E, Liu J, Sherman DR, Behr MA (2004) Impact of methoxymycolic acid production by Mycobacterium bovis BCG vaccines. Infect Immun 72:2803–2809CrossRefPubMedPubMedCentralGoogle Scholar
  16. Brewer TF (2000) Preventing tuberculosis with Bacillus Calmette-Guerin vaccine: a meta-analysis of the literature. Clin Infect Dis 31(Suppl 3):S64–S67Google Scholar
  17. Brosch R, Gordon SV, Buchrieser C, Pym AS, Garnier T, Cole ST (2000) Comparative genomics uncovers large tandem chromosomal duplications in Mycobacterium bovis BCG Pasteur. Yeast 17:111–123CrossRefPubMedPubMedCentralGoogle Scholar
  18. Brosch R, Gordon SV, Garnier T, Eiglmeier K, Frigui W, VALENTI P, Dos Santos S, Duthoy S, Lacroix C, Garcia-Pelayo C, Inwald JK, Golby P, Garcia JN, Hewinson RG, Behr MA, Quail MA, Churcher C, Barrell BG, Parkhill J, Cole ST (2007) Genome plasticity of BCG and impact on vaccine efficacy. Proc Natl Acad Sci U S A 104:5596–5601CrossRefPubMedPubMedCentralGoogle Scholar
  19. Bryder L (1999) ‘We shall not find salvation in inoculation’: BCG vaccination in Scandinavia, Britain and the USA, 1921–1960. Soc Sci Med 49:1157–1167CrossRefPubMedGoogle Scholar
  20. Calmette A (1922) L’ninfection bacillaire et la tuberculose chez l’homme et chez les animauxGoogle Scholar
  21. Calmette A, Guerin C, Weill-Halle B (1924) Essai d’immunisation contre l’infection tuberculeuse. Bull Acad Med Paris 91:787–796Google Scholar
  22. Charlet D, Mostowy S, Alexander D, Sit L, Wiker HG, Behr MA (2005) Reduced expression of antigenic proteins MPB70 and MPB83 in Mycobacterium bovis BCG strains due to a start codon mutation in sigK. Mol Microbiol 56:1302–1313CrossRefPubMedGoogle Scholar
  23. Chen JM, Islam ST, Ren H, Liu J (2007) Differential productions of lipid virulence factors among BCG vaccine strains and implications on BCG safety. Vaccine 25:8114–8122CrossRefPubMedGoogle Scholar
  24. Chen JM, Uplekar S, Gordon SV, Cole ST (2012) A point mutation in cycA partially contributes to the D-cycloserine resistance trait of Mycobacterium bovis BCG vaccine strains. PLoS One 7:e43467CrossRefPubMedPubMedCentralGoogle Scholar
  25. Colditz GA, Berkey CS, Mosteller F, Brewer TF, Wilson ME, Burdick E, Fineberg HV (1995) The efficacy of bacillus Calmette-Guerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature. Pediatrics 96:29–35PubMedGoogle Scholar
  26. Corbel MJ, Fruth U, Griffiths E, Knezevic I (2004) Report on a WHO consultation on the characterisation of BCG strains, Imperial College, London 15–16 December 2003. Vaccine 22:2675–2680CrossRefPubMedGoogle Scholar
  27. Dreyer G, Vollum RL (1931) Mutation and pathogenicity experiments with BC G. Lancet 1:9–15CrossRefGoogle Scholar
  28. Dubos RJ, Pierce CH (1956) Differential characteristics in vitro and in vivo of several substrains of BCG. IV. Immunizing effectiveness. Am Rev Tuberc 74:699–717PubMedGoogle Scholar
  29. Fernandes ND, Wu QL, Kong D, Puyang X, Garg S, Husson RN (1999) A mycobacterial extracytoplasmic sigma factor involved in survival following heat shock and oxidative stress. J Bacteriol 181:4266–4274PubMedPubMedCentralGoogle Scholar
  30. Fine PE (1995) Variation in protection by BCG: implications of and for heterologous immunity. Lancet 346:1339–1345CrossRefPubMedGoogle Scholar
  31. Frothingham R, Hills HG, Wilson KH (1994) Extensive DNA sequence conservation throughout the Mycobacterium tuberculosis complex. J Clin Microbiol 32:1639–1643PubMedPubMedCentralGoogle Scholar
  32. Garnier T, Eiglmeier K, Camus JC, Medina N, Mansoor H, Pryor M, Duthoy S, Grondin S, Lacroix C, Monsempe C, Simon S, Harris B, Atkin R, Doggett J, Mayes R, Keating L, Wheeler PR, Parkhill J, Barrell BG, Cole ST, Gordon SV, Hewinson RG (2003) The complete genome sequence of Mycobacterium bovis. Proc Natl Acad Sci U S A 100:7877–7882CrossRefPubMedPubMedCentralGoogle Scholar
  33. Gheorghiu M, Augier J, Lagrange PH (1983) Maintenance and control of the French Bcg strain 1173-P2 (primary and secondary seed-lots). Bull Inst Pasteur 81: 281–288Google Scholar
  34. Gordon SV, Brosch R, Billault A, Garnier T, Eiglmeier K, Cole ST (1999) Identification of variable regions in the genomes of tubercle bacilli using bacterial artificial chromosome arrays. Mol Microbiol 32:643–655CrossRefPubMedGoogle Scholar
  35. Grange JM, Gibson J, Osborn TW, Collins CH, Yates MD (1983) What is BCG? Tubercle 64:129–139CrossRefPubMedGoogle Scholar
  36. Griffin JF, Chinn DN, Rodgers CR, Mackintosh CG (2001) Optimal models to evaluate the protective efficacy of tuberculosis vaccines. Tuberculosis (Edinb) 81:133–139CrossRefGoogle Scholar
  37. Guinn KM, Hickey MJ, Mathur SK, Zakel KL, Grotzke JE, Lewinsohn DM, Smith S, Sherman DR (2004) Individual RD1-region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis. Mol Microbiol 51:359–370CrossRefPubMedPubMedCentralGoogle Scholar
  38. Gupta S, Sinha A, Sarkar D (2006) Transcriptional autoregulation by Mycobacterium tuberculosis PhoP involves recognition of novel direct repeat sequences in the regulatory region of the promoter. FEBS Lett 580:5328–5338CrossRefPubMedGoogle Scholar
  39. Hsu T, Hingley-Wilson SM, Chen B, Chen M, Dai AZ, Morin PM, Marks CB, Padiyar J, Goulding C, Gingery M, Eisenberg D, Russell RG, Derrick SC, Collins FM, Morris SL, King CH, Jacobs WR Jr (2003) The primary mechanism of attenuation of bacillus Calmette-Guerin is a loss of secreted lytic function required for invasion of lung interstitial tissue. Proc Natl Acad Sci U S A 100:12420–12425CrossRefPubMedPubMedCentralGoogle Scholar
  40. Huard RC, Fabre M, De Haas P, Lazzarini LCO, Van Soolingen D, Cousins D, Ho JL (2006) Novel genetic polymorphisms that further delineate the phylogeny of the Mycobacterium tuberculosis complex. J Bacteriol 188:4271–4287CrossRefPubMedPubMedCentralGoogle Scholar
  41. Hunt DM, Saldanha JW, Brennan JF, Benjamin P, Strom M, Cole JA, Spreadbury CL, Buxton RS (2008) Single nucleotide polymorphisms that cause structural changes in the cyclic AMP receptor protein transcriptional regulator of the tuberculosis vaccine strain Mycobacterium bovis BCG alter global gene expression without attenuating growth. Infect Immun 76:2227–2234CrossRefPubMedPubMedCentralGoogle Scholar
  42. Imaeda T, Coppola KM, Furness G (1985) Deoxyribonucleic acids of Corynebacterium genitalium and Corynebacterium pseudogenitalium: their genome molecular weights, base ratios, and DNA relatedness with other corynebacteria involved in urinary tract infections. Can J Microbiol 31:1068–1070CrossRefPubMedGoogle Scholar
  43. Kaufmann SHE, Winau F (2005) From bacteriology to immunology: the dualism of specificity. Nat Immunol 6:1063–1066CrossRefPubMedGoogle Scholar
  44. Kaufmann SHE, Hussey G, Lambert PH (2010) New vaccines for tuberculosis. Lancet 375:2110–2119CrossRefPubMedGoogle Scholar
  45. Keating LA, Wheeler PR, Mansoor H, Inwald JK, Dale J, Hewinson RG, Gordon SV (2005) The pyruvate requirement of some members of the Mycobacterium tuberculosis complex is due to an inactive pyruvate kinase: implications for in vivo growth. Mol Microbiol 56:163–174CrossRefPubMedGoogle Scholar
  46. Keller PM, Bottger EC, Sander P (2008) Tuberculosis vaccine strain Mycobacterium bovis BCG Russia is a natural recA mutant. BMC Microbiol 8:120CrossRefPubMedPubMedCentralGoogle Scholar
  47. Kolibab K, Derrick SC, Morris SL (2011) Sensitivity to isoniazid of Mycobacterium bovis BCG strains and BCG disseminated disease isolates. J Clin Microbiol 49:2380–2381CrossRefPubMedPubMedCentralGoogle Scholar
  48. Kozak R, Behr MA (2011) Divergence of immunologic and protective responses of different BCG strains in a murine model. Vaccine 29:1519–1526CrossRefPubMedGoogle Scholar
  49. Kozak RA, Alexander DC, Liao R, Sherman DR, Behr MA (2011) Region of difference 2 contributes to virulence of Mycobacterium tuberculosis. Infect Immun 79:59–66CrossRefPubMedGoogle Scholar
  50. Ladefoged A, Bunch-Christensen K, Guld J (1976) Tuberculin sensitivity in guinea-pigs after vaccination with varying doses of BCG of 12 different strains. Bull World Health Organ 53:435–443PubMedPubMedCentralGoogle Scholar
  51. Leung AS, Tran V, Wu Z, Yu X, Alexander DC, Gao GF, Zhu B, Liu J (2008) Novel genome polymorphisms in BCG vaccine strains and impact on efficacy. BMC Genomics 9:413CrossRefPubMedPubMedCentralGoogle Scholar
  52. Lewis KN, Liao R, Guinn KM, Hickey MJ, Smith S, Behr MA, Sherman DR (2003) Deletion of RD1 from Mycobacterium tuberculosis mimics bacille Calmette-Guerin attenuation. J Infect Dis 187:117–123CrossRefPubMedGoogle Scholar
  53. Lind A (1983) The Swedish strain of Bcg. Tubercle 64:233–234CrossRefGoogle Scholar
  54. Liu J, Tran V, Leung AS, Alexander DC, Zhu B (2009) BCG vaccines: their mechanisms of attenuation and impact on safety and protective efficacy. Hum Vaccin 5:70–78CrossRefPubMedGoogle Scholar
  55. Lotte A, Wasz-Hockert O, Poisson N, Dumitrescu N, Verron M, Couvet E (1984) BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv Tuberc Res 21:107–193PubMedGoogle Scholar
  56. Mahairas GG, Sabo PJ, Hickey MJ, Singh DC, Stover CK (1996) Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M-bovis. J Bacteriol 178:1274–1282CrossRefPubMedPubMedCentralGoogle Scholar
  57. Matsunaga I, Bhatt A, Young DC, Cheng TY, Eyles SJ, Besra GS, Briken V, Porcelli SA, Costello CE, Jacobs WR Jr, Moody DB (2004) Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T cells. J Exp Med 200:1559–1569CrossRefPubMedPubMedCentralGoogle Scholar
  58. Mcshane H (2011) Tuberculosis vaccines: beyond bacille Calmette-Guerin. Philos Trans R Soc Lond Ser B Biol Sci 366:2782–2789CrossRefGoogle Scholar
  59. Milstien JB, Gibson JJ (1990) Quality control of BCG vaccine by WHO: a review of factors that may influence vaccine effectiveness and safety. Bull World Health Organ 68:93–108PubMedPubMedCentralGoogle Scholar
  60. Mostowy S, Tsolaki AG, Small PM, Behr MA (2003) The in vitro evolution of BCG vaccines. Vaccine 21:4270–4274CrossRefPubMedGoogle Scholar
  61. Munoz ME, Ponce E (2003) Pyruvate kinase: current status of regulatory and functional properties. Comp Biochem Physiol B Biochem Mol Biol 135:197–218CrossRefPubMedGoogle Scholar
  62. Naka T, Maeda S, Niki M, Ohara N, Yamamoto S, Yano I, Maeyama J, Ogura H, Kobayashi K, Fujiwara N (2011) Lipid phenotype of two distinct subpopulations of Mycobacterium bovis Bacillus Calmette-Guerin Tokyo 172 substrain. J Biol Chem 286:44153–44161CrossRefPubMedPubMedCentralGoogle Scholar
  63. Obayashi Y (1955) Dried BCG vaccine. Monogr Ser World Health Organ, 1–220Google Scholar
  64. Oettinger T, Jorgensen M, Ladefoged A, Haslov K, Andersen P (1999) Development of the Mycobacterium bovis BCG vaccine: review of the historical and biochemical evidence for a genealogical tree. Tuber Lung Dis 79:243–250CrossRefPubMedGoogle Scholar
  65. Ottenhoff TH (2009) Overcoming the global crisis: “yes, we can”, but also for TB ... ? Eur J Immunol 39:2014–2020CrossRefPubMedGoogle Scholar
  66. Ottenhoff THM, Kaufmann SHE (2012) Vaccines against tuberculosis: where are we and where do we need to go? PLoS Pathog 8Google Scholar
  67. Parish T, Smith DA, Kendall S, Casali N, Bancroft GJ, Stoker NG (2003) Deletion of two-component regulatory systems increases the virulence of Mycobacterium tuberculosis. Infect Immun 71:1134–1140CrossRefPubMedPubMedCentralGoogle Scholar
  68. Pelayo MCG, Uplekar S, Keniry A, Lopez PM, Garnier T, Garcia JN, Boschiroli L, Zhou XM, Parkhill J, Smith N, Hewinson RG, Cole ST, Gordon SV (2009) A comprehensive survey of single nucleotide polymorphisms (SNPs) across Mycobacterium bovis strains and M. bovis BCG vaccine strains refines the genealogy and defines a minimal set of SNPs that separate virulent M. bovis strains and M. bovis BCG strains. Infect Immun 77:2230–2238CrossRefGoogle Scholar
  69. Pym AS, Brodin P, Majlessi L, Brosch R, Demangel C, Williams A, Griffiths KE, Marchal G, Leclerc C, Cole ST (2003) Recombinant BCG exporting ESAT-6 confers enhanced protection against tuberculosis. Nat Med 9:533–539CrossRefPubMedGoogle Scholar
  70. Rosenthal SR, Loewinsohne, Graham ML, Liveright D, Thorne G, Johnson V (1961) BCG vaccination against tuberculosis in Chicago. A twenty-year study statistically analyzed. Pediatrics 28:622–641PubMedGoogle Scholar
  71. Sakula A (1983) BCG: who were Calmette and Guerin? Thorax 38:806–812CrossRefPubMedPubMedCentralGoogle Scholar
  72. Salamon H, Kato-Maeda M, Small PM, Drenkow J, Gingeras TR (2000) Detection of deleted genomic DNA using a semiautomated computational analysis of GeneChip data. Genome Res 10:2044–2054CrossRefPubMedPubMedCentralGoogle Scholar
  73. Sherman DR, Guinn KM, Hickey MJ, Mathur SK, Zakel KL, Smith S (2004) Mycobacterium tuberculosis H37Rv: Delta RD1 is more virulent than M. bovis bacille Calmette-Guerin in long-term murine infection. J Infect Dis 190:123–126CrossRefPubMedPubMedCentralGoogle Scholar
  74. Singh A, Crossman DK, Mai D, Guidry L, Voskuil MI, Renfrow MB, Steyn AJ (2009) Mycobacterium tuberculosis WhiB3 maintains redox homeostasis by regulating virulence lipid anabolism to modulate macrophage response. PLoS Pathog 5:e1000545CrossRefPubMedPubMedCentralGoogle Scholar
  75. Sinha A, Gupta S, Bhutani S, Pathak A, Sarkar D (2008) PhoP-PhoP interaction at adjacent PhoP binding sites is influenced by protein phosphorylation. J Bacteriol 190:1317–1328CrossRefPubMedGoogle Scholar
  76. Stanley SA, Raghavan S, Hwang WW, Cox JS (2003) Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system. Proc Natl Acad Sci U S A 100:13001–13006CrossRefPubMedPubMedCentralGoogle Scholar
  77. Stewart GR, Snewin VA, Walzl G, Hussell T, Tormay P, O’Gaora P, Goyal M, Betts J, Brown IN, Young DB (2001) Overexpression of heat-shock proteins reduces survival of Mycobacterium tuberculosis in the chronic phase of infection. Nat Med 7:732–737CrossRefPubMedGoogle Scholar
  78. Stewart GR, Wernisch L, Stabler R, Mangan JA, Hinds J, Laing KG, Young DB, Butcher PD (2002) Dissection of the heat-shock response in Mycobacterium tuberculosis using mutants and microarrays. Microbiology 148:3129–3138CrossRefPubMedGoogle Scholar
  79. Steyn AJ, Collins DM, Hondalus MK, Jacobs WR Jr, Kawakami RP, Bloom BR (2002) Mycobacterium tuberculosis WhiB3 interacts with RpoV to affect host survival but is dispensable for in vivo growth. Proc Natl Acad Sci U S A 99:3147–3152CrossRefPubMedPubMedCentralGoogle Scholar
  80. Takayama K, Wang L, David HL (1972) Effect of isoniazid on the in vivo mycolic acid synthesis, cell growth, and viability of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2:29–35CrossRefPubMedPubMedCentralGoogle Scholar
  81. Tran V, Ahn SK, Ng M, Li M, Liu J (2016) Loss of lipid virulence factors reduces the efficacy of the BCG vaccine. Sci Rep 6:29076CrossRefPubMedPubMedCentralGoogle Scholar
  82. Trunz BB, Fine P, Dye C (2006) Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet 367:1173–1180CrossRefPubMedGoogle Scholar
  83. Vallishayee RS, Shashidhara AN, Bunch-Christensen K, Guld J (1974) Tuberculin sensitivity and skin lesions in children after vaccination with 11 different BCG strains. Bull World Health Organ 51:489–494PubMedPubMedCentralGoogle Scholar
  84. Wallgren A (1928) Intradermal vaccinations with BCG virus – preliminary note. J Am Med Assoc 91:1876–1881CrossRefGoogle Scholar
  85. Walters SB, Dubnau E, Kolesnikova I, Laval F, Daffe M, Smith I (2006) The Mycobacterium tuberculosis PhoPR two-component system regulates genes essential for virulence and complex lipid biosynthesis. Mol Microbiol 60:312–330CrossRefPubMedGoogle Scholar
  86. Wang S, Engohang-Ndong J, Smith I (2007) Structure of the DNA-binding domain of the response regulator PhoP from Mycobacterium tuberculosis. Biochemistry 46:14751–14761CrossRefPubMedPubMedCentralGoogle Scholar
  87. Wernisch L, Kendall SL, Soneji S, Wietzorrek A, Parish T, Hinds J, Butcher PD, Stoker NG (2003) Analysis of whole-genome microarray replicates using mixed models. Bioinformatics 19:53–61CrossRefPubMedGoogle Scholar
  88. Wiker HG, Nagai S, Hewinson RG, Russell WP, Harboe M (1996) Heterogenous expression of the related MPB70 and MPB83 proteins distinguish various substrains of Mycobacterium bovis BCG and Mycobacterium tuberculosis H37Rv. Scand J Immunol 43:374–380CrossRefPubMedGoogle Scholar
  89. Zwaig N, Kistler WS, Lin EC (1970) Glycerol kinase, the pacemaker for the dissimilation of glycerol in Escherichia coli. J Bacteriol 102:753–759PubMedPubMedCentralGoogle Scholar
  90. Zwerling A, Behr MA, Verma A, Brewer TF, Menzies D, Pai M (2011) The BCG world atlas: a database of global BCG vaccination policies and practices. PLoS Med 8:e1001012CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Bioscience Core LaboratoryKing Abdullah University of Science and TechnologyJeddahKingdom of Saudi Arabia
  2. 2.Department of MedicineMcGill University Health CentreMontrealCanada

Personalised recommendations