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

Single nucleotide polymorphisms (SNPs) are present in the global transcriptional regulator cyclic AMP (cAMP) receptor protein (CRP) of the attenuated vaccine strain Mycobacterium bovis, bacillus Calmette-Guérin (BCG). We have found that these SNPs resulted in small but significant changes in the exp...

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Bibliographic Details
Published in:Infection and Immunity 2008-05, Vol.76 (5), p.2227-2234
Main Authors: Hunt, Debbie M, Saldanha, José W, Brennan, John F, Benjamin, Pearline, Strom, Molly, Cole, Jeffrey A, Spreadbury, Claire L, Buxton, Roger S
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino Acid Substitution - genetics
Animals
Bacterial diseases
Bacteriology
Biological and medical sciences
Cells, Cultured
Cyclic AMP - metabolism
Cyclic AMP Receptor Protein - chemistry
Cyclic AMP Receptor Protein - genetics
Cyclic AMP Receptor Protein - metabolism
DNA, Bacterial - metabolism
Escherichia coli
Female
Fundamental and applied biological sciences. Psychology
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation, Bacterial
Genetic Complementation Test
Human bacterial diseases
Infectious diseases
Macrophages - microbiology
Medical sciences
Mice
Mice, Inbred BALB C
Microbiology
Miscellaneous
Models, Molecular
Molecular Pathogenesis
Molecular Sequence Data
Mycobacterium bovis
Mycobacterium bovis - genetics
Mycobacterium bovis - pathogenicity
Mycobacterium bovis - physiology
Mycobacterium Infections - microbiology
Mycobacterium tuberculosis - genetics
Mycobacterium tuberculosis - growth & development
Polymorphism, Single Nucleotide
Protein Binding
Protein Structure, Tertiary
Sequence Alignment
Tuberculosis and atypical mycobacterial infections
Virulence
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Summary:Single nucleotide polymorphisms (SNPs) are present in the global transcriptional regulator cyclic AMP (cAMP) receptor protein (CRP) of the attenuated vaccine strain Mycobacterium bovis, bacillus Calmette-Guérin (BCG). We have found that these SNPs resulted in small but significant changes in the expression of a number of genes in M. tuberculosis when a deletion of the Rv3676 CRP was complemented by the BCG allele, compared to complementation by the M. tuberculosis allele. We can explain these changes in gene expression by modeling the structure of the mycobacterial protein on the known structure of CRP from Escherichia coli. Thus, the SNP change in the DNA-binding domain, Lys178, is predicted to form a hydrogen bond with the phosphate backbone of the DNA, as does the equivalent residue in E. coli, whereas Glu178 in M. tuberculosis/M. bovis does not, thus explaining the stronger binding reported for CRP of BCG to CRP-binding sites in mycobacterial DNA. In contrast, the SNP change in the nucleotide binding domain (Leu47Pro) is predicted to result in the loss of one hydrogen bond, which is accommodated by the structure, and would not therefore be expected to cause any change in function relating to cAMP binding. The BCG allele fully complemented the growth defect caused by the deletion of the Rv3676 protein in M. tuberculosis, both in vitro and in macrophage and mouse infections, suggesting that these SNPs do not play any role in the attenuation of BCG. However, they may have allowed BCG to grow better under the in vitro-selective conditions used in its derivation from the M. bovis wild type.
ISSN:0019-9567
1098-5522
DOI:10.1128/IAI.01410-07