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Science 28 May 1999:
Vol. 284. no. 5419, pp. 1520 - 1523
DOI: 10.1126/science.284.5419.1520
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Reports

Comparative Genomics of BCG Vaccines by Whole-Genome DNA Microarray

M. A. Behr, 1*dagger M. A. Wilson, 2dagger W. P. Gill, 2 H. Salamon, 2 G. K. Schoolnik, 2 S. Rane, 2 P. M. Small 2

Bacille Calmette-Guérin (BCG) vaccines are live attenuated strains of Mycobacterium bovis administered to prevent tuberculosis. To better understand the differences between M. tuberculosis, M. bovis, and the various BCG daughter strains, their genomic compositions were studied by performing comparative hybridization experiments on a DNA microarray. Regions deleted from BCG vaccines relative to the virulent M. tuberculosis H37Rv reference strain were confirmed by sequencing across the missing segment of the H37Rv genome. Eleven regions (encompassing 91 open reading frames) of H37Rv were found that were absent from one or more virulent strains of M. bovis. Five additional regions representing 38 open reading frames were present in M. bovis but absent from some or all BCG strains; this is evidence for the ongoing evolution of BCG strains since their original derivation. A precise understanding of the genetic differences between closely related Mycobacteria suggests rational approaches to the design of improved diagnostics and vaccines.

1 Division of Infectious Diseases, Department of Medicine, McGill University Health Centre, Montreal H3G 1A4, Canada.
2 Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
*   To whom correspondence should be addressed. E-mail: mbgq{at}musica.mcgill.ca

dagger    These authors contributed equally to this report.

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Am. J. Respir. Crit. Care Med. 171, 1436-1442
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Discrepancy Between the Tuberculin Skin Test and the Whole-Blood Interferon {gamma} Assay for the Diagnosis of Latent Tuberculosis Infection in an Intermediate Tuberculosis-Burden Country.
Y. A. Kang, H. W. Lee, H. I. Yoon, B. Cho, S. K. Han, Y.-S. Shim, and J.-J. Yim (2005)
JAMA 293, 2756-2761
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Efficient Ex Vivo Stimulation of Mycobacterium tuberculosis-Specific T Cells by Genetically Detoxified Bordetella pertussis Adenylate Cyclase Antigen Toxoids.
K. A. Wilkinson, M. Simsova, E. Scholvinck, P. Sebo, C. Leclerc, H. M. Vordermeier, S. J. Dickson, J. R. Brown, R. N. Davidson, G. Pasvol, et al. (2005)
Infect. Immun. 73, 2991-2998
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Prospective Evaluation of a Whole-Blood Test Using Mycobacterium tuberculosis-Specific Antigens ESAT-6 and CFP-10 for Diagnosis of Active Tuberculosis.
P. Ravn, M. E. Munk, A. B. Andersen, B. Lundgren, J. D. Lundgren, L. N. Nielsen, A. Kok-Jensen, P. Andersen, and K. Weldingh (2005)
Clin. Vaccine Immunol. 12, 491-496
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The Pathogenesis of Tuberculosis: The First One Hundred (and Twenty-Three) Years.
N. W. Schluger (2005)
Am. J. Respir. Cell Mol. Biol. 32, 251-256
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Influence of ESAT-6 Secretion System 1 (RD1) of Mycobacterium tuberculosis on the Interaction between Mycobacteria and the Host Immune System.
L. Majlessi, P. Brodin, R. Brosch, M.-J. Rojas, H. Khun, M. Huerre, S. T. Cole, and C. Leclerc (2005)
J. Immunol. 174, 3570-3579
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Compiling a Molecular Inventory for Mycobacterium bovis BCG at Two Growth Rates: Evidence for Growth Rate-Mediated Regulation of Ribosome Biosynthesis and Lipid Metabolism.
D. J. V. Beste, J. Peters, T. Hooper, C. Avignone-Rossa, M. E. Bushell, and J. McFadden (2005)
J. Bacteriol. 187, 1677-1684
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Transcriptome of Treponema pallidum: Gene Expression Profile during Experimental Rabbit Infection.
D. Smajs, M. McKevitt, J. K. Howell, S. J. Norris, W.-W. Cai, T. Palzkill, and G. M. Weinstock (2005)
J. Bacteriol. 187, 1866-1874
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Long-Term Protection against Tuberculosis following Vaccination with a Severely Attenuated Double Lysine and Pantothenate Auxotroph of Mycobacterium tuberculosis.
V. K. Sambandamurthy, S. C. Derrick, K. V. Jalapathy, B. Chen, R. G. Russell, S. L. Morris, and W. R. Jacobs Jr. (2005)
Infect. Immun. 73, 1196-1203
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Point mutations in the DNA- and cNMP-binding domains of the homologue of the cAMP receptor protein (CRP) in Mycobacterium bovis BCG: implications for the inactivation of a global regulator and strain attenuation.
C. L. Spreadbury, M. J. Pallen, T. Overton, M. A. Behr, S. Mostowy, S. Spiro, S. J. W. Busby, and J. A. Cole (2005)
Microbiology 151, 547-556
   Abstract »    Full Text »    PDF »
ArrayOme: a program for estimating the sizes of microarray-visualized bacterial genomes.
H.-Y. Ou, R. Smith, S. Lucchini, J. Hinton, R. R. Chaudhuri, M. Pallen, M. R. Barer, and K. Rajakumar (2005)
Nucleic Acids Res. 33, e3
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Assessing the Serodiagnostic Potential of 35 Mycobacterium tuberculosis Proteins and Identification of Four Novel Serological Antigens.
K. Weldingh, I. Rosenkrands, L. M. Okkels, T. M. Doherty, and P. Andersen (2005)
J. Clin. Microbiol. 43, 57-65
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Gene expression diversity among Mycobacterium tuberculosis clinical isolates.
Q. Gao, K. E. Kripke, A. J. Saldanha, W. Yan, S. Holmes, and P. M. Small (2005)
Microbiology 151, 5-14
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Multiplex PCR-Identified Cutaneous Tuberculosis Evoked by Mycobacterium bovis BCG Vaccination in a Healthy Baby.
T. Okazaki, S. Ebihara, H. Takahashi, M. Asada, A. Sato, M. Seki, H. Ohto, and H. Sasaki (2005)
J. Clin. Microbiol. 43, 523-525
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Single Mucosal, but Not Parenteral, Immunization with Recombinant Adenoviral-Based Vaccine Provides Potent Protection from Pulmonary Tuberculosis.
J. Wang, L. Thorson, R. W. Stokes, M. Santosuosso, K. Huygen, A. Zganiacz, M. Hitt, and Z. Xing (2004)
J. Immunol. 173, 6357-6365
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Recognition of Mycobacterial Antigens Delivered by Genetically Detoxified Bordetella pertussis Adenylate Cyclase by T Cells from Cattle with Bovine Tuberculosis.
H. M. Vordermeier, M. Simsova, K. A. Wilkinson, R. J. Wilkinson, R. G. Hewinson, P. Sebo, and C. Leclerc (2004)
Infect. Immun. 72, 6255-6261
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The Protective Effect of the Mycobacterium bovis BCG Vaccine Is Increased by Coadministration with the Mycobacterium tuberculosis 72-Kilodalton Fusion Polyprotein Mtb72F in M. tuberculosis-Infected Guinea Pigs.
L. Brandt, Y. A. W. Skeiky, M. R. Alderson, Y. Lobet, W. Dalemans, O. C. Turner, R. J. Basaraba, A. A. Izzo, T. M. Lasco, P. L. Chapman, et al. (2004)
Infect. Immun. 72, 6622-6632
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Mycobacterium africanum Genotyping Using Novel Spacer Oligonucleotides in the Direct Repeat Locus.
K. Brudey, M. C. Gutierrez, V. Vincent, L. M. Parsons, M. Salfinger, N. Rastogi, and C. Sola (2004)
J. Clin. Microbiol. 42, 5053-5057
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Patterns of large-scale genomic variation in virulent and avirulent Burkholderia species.
C. Ong, C. H. Ooi, D. Wang, H. Chong, K. C. Ng, F. Rodrigues, M. A. Lee, and P. Tan (2004)
Genome Res. 14, 2295-2307
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Large-Scale Comparative Genomics Meta-Analysis of Campylobacter jejuni Isolates Reveals Low Level of Genome Plasticity.
E. N. Taboada, R. R. Acedillo, C. D. Carrillo, W. A. Findlay, D. T. Medeiros, O. L. Mykytczuk, M. J. Roberts, C. A. Valencia, J. M. Farber, and J. H. E. Nash (2004)
J. Clin. Microbiol. 42, 4566-4576
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Extensive Genomic Polymorphism within Mycobacterium avium.
M. Semret, G. Zhai, S. Mostowy, C. Cleto, D. Alexander, G. Cangelosi, D. Cousins, D. M. Collins, D. van Soolingen, and M. A. Behr (2004)
J. Bacteriol. 186, 6332-6334
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The RD1 virulence locus of Mycobacterium tuberculosis regulates DNA transfer in Mycobacterium smegmatis.
J. L. Flint, J. C. Kowalski, P. K. Karnati, and K. M. Derbyshire (2004)
PNAS 101, 12598-12603
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DNA Microarray-Based Genome Comparison of a Pathogenic and a Nonpathogenic Strain of Xylella fastidiosa Delineates Genes Important for Bacterial Virulence.
T. Koide, P. A. Zaini, L. M. Moreira, R. Z. N. Vencio, A. Y. Matsukuma, A. M. Durham, D. C. Teixeira, H. El-Dorry, P. B. Monteiro, A. C. R. da Silva, et al. (2004)
J. Bacteriol. 186, 5442-5449
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Genomic Analysis Distinguishes Mycobacterium africanum.
S. Mostowy, A. Onipede, S. Gagneux, S. Niemann, K. Kremer, E. P. Desmond, M. Kato-Maeda, and M. Behr (2004)
J. Clin. Microbiol. 42, 3594-3599
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