Impact of Methoxymycolic Acid Production by
            <i>Mycobacterium bovis</i>
            BCG Vaccines

Belley, Adam; Alexander, David C.; Pietrantonio, Tania Di; Girard, Manon; Jones, Joses R. W.; Schurr, Erwin; Liu, Jun; Sherman, David R.; Behr, Marcel A.

doi:10.1128/iai.72.5.2803-2809.2004

Cited by 29 publications

(29 citation statements)

References 31 publications

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“…Intriguingly, the loss of methoxymycolate appears to have no impact on the virulence of late BCG strains. 51 PDIMs/PGLs. The direct evidence that BCG strains differ in established virulence factors first came from the comparative biochemical analysis of phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs).…”

Section: Bcg: a Brief Historymentioning

confidence: 99%

BCG Vaccines: Their mechanisms of attenuation and impact on safety and protective efficacy

Liu

Tran²,

Leung³

et al. 2009

Human Vaccines

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by MDR strains that are also resistant to a fluoroquinolone and at least one second-line injectable agent (amikacin, kanamycin and/or capreomycin), caught the world's attention after an outbreak in KwaZulu-Natal, South Africa, where 52 of 53 infected patients died. 2 HIV co-infection was a contributing factor in most of these deaths, and indeed, a deadly association between HIV and TB has been known almost since the start of the HIV-epidemic. Of the 1.7 million people who died from TB in 2006, an estimated 200,000 were co-infected with HIV. 1 Because of these situations, effective approaches alternative to antibiotics are urgently needed for the control of TB.Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis (M. bovis), is currently the only available vaccine against TB. Since 1974, BCG vaccination has been included in the WHO Expanded Program on Immunization. 3 It is estimated that more than 3 billion individuals have been immunized with BCG and over 100 million doses of BCG are administered annually, making it the most widely used vaccine in humans. 3 Meta-analysis studies have confirmed that BCG protects children, providing >80% efficacy against severe forms of TB, including tuberculous meningitis and miliary TB. 4,5 In contrast, evidence for protection against pulmonary TB in adolescents and adults remains contentious as efficacy estimates from clinical trials, observational case control studies and contact studies range from 0 to 80%. 6,7 The reasons for the variable protective efficacy are unknown but several hypotheses have been proposed, including differences among the vaccine strains used in clinical studies, exposure of trial populations to environmental mycobacteria, nutritional or genetic differences in human populations, differences in trial methods, and variations among clinical M. tb strains. 8-13 These explanations are not mutually exclusive and all may contribute to the heterogeneity in vaccine efficacy.A key aspect of this issue may concern the nature of BCG attenuation. Although it is generally considered safe and has been used as a human vaccine since the 1920s, the mechanisms of BCG attenuation remain largely unknown. This is further complicated by the fact that BCG is not a single strain, but instead comprises a number of substrains that exhibit phenotypic and biochemical differences. 14 BCG strains also exhibit differences in residual virulence level. [15][16][17] However, side effects were often attributed to variations in the viability of vaccines during preparation procedures (e.g., freezedrying). 14 In other words, the observed differential virulence among Mycobacterium bovis Bacille Calmette-Guérin (BCG) was developed as an attenuated live vaccine for tuberculosis control nearly a century ago. Despite being the most widely used vaccine in human history, the mechanisms of attenuation of BCG remain poorly understood. BCG is not a single organism, but comprises a number of substrains that differ in genotypes and phenotypes. The impacts of these differences on BCG...

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Section: Bcg: a Brief Historymentioning

confidence: 99%

BCG Vaccines: Their mechanisms of attenuation and impact on safety and protective efficacy

Liu

Tran²,

Leung³

et al. 2009

Human Vaccines

Self Cite

123

117

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“…Of note, this digestion completely removes the tetRO module. After transformation in E. coli, verification by PCR, and restriction digestion, plasmids were electroporated into M. tuberculosis H37Ra, BCG Pasteur, and BCG Russia as previously described (3). Hygromicin-and kanamycin-resistant clones were selected for further experiments.…”

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confidence: 99%

Evolution of the Mycobacterial SigK Regulon

2008

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Previous studies have established that members of the Mycobacterium tuberculosis complex exhibit variable production of the antigenic proteins MPT70 and MPT83 due to mutations in their positive regulator, SigK (sigma factor K), and their negative regulator, RskA (regulator of sigma K). To further understand this highly specific SigK-controlled regulon, we have undertaken evolutionary studies to determine the presence of homologues of SigK-regulated genes in other organisms and to predict its transcriptional network. Evolutionary analysis indicates that the positive and negative regulators are conserved across many organisms, but that the genes under their control are variable. Moreover, the addition, loss, and movement of various genes in the mpt70/83 locus suggest that these genes are unlikely to be cotranscribed. To test predictions from sequence analysis, we have used promoter luciferase fusions and Northern blots to show that the majority of genes in this locus have their own promoters, of which a subset are SigK regulated (mpt83, dipZ, mpt70, and Rv0449c). Next, we have shown that the intracellular inducibility of mpt70 and mpt83 is a conserved property, shared between M. tuberculosis and Mycobacterium marinum. In addition, we have shown that SigK and RskA from an environmental mycobacterium isolate (M. gilvum PYR-GCK) complemented the regulatory activity of M. tuberculosis ⌬sigK rskA. Together, our data indicate that the regulatory system SigK/RskA is conserved across the Mycobacterium genus, whereas the regulon under its control varies considerably across species.Mycobacterium tuberculosis is an extremely successful pathogen of humans, infecting an estimated one-third of the world's population. This capacity to persist in the host, despite the dynamic alterations effected by the host immune response, testifies to an evolved capacity of the organism to regulate its genetic expression to the conditions encountered during infection. Indeed, a number of studies have demonstrated that disruption of M. tuberculosis regulatory elements, such as sigma factors, results in reduced virulence in experimental models (21,28,30).The determination of genomic sequences for a number of nonpathogenic mycobacteria has revealed that homologues of many genes, including regulatory elements, are often present in organisms that are not virulent to humans. For instance, comparative analysis has demonstrated conservation of biochemical pathways and a secretory system important for full virulence of M. tuberculosis (7,10). This indicates that genetic elements and the proteins they encode that exist in other mycobacteria either serve an important function in M. tuberculosis pathogenicity or have evolved a specific role in M. tuberculosis complex organisms. As a number of predicted regulatory elements are also conserved between environmental mycobacteria and M. tuberculosis, it follows that an evolutionary analysis may guide predictions about the origins of such elements, the transcriptional networks they control, and the stimuli that...

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“…None-the-less, the addition of M. tuberculosis specific genes to BCG is a powerful means to analyse gene function and define virulence determinants (3,20). While much attention has been on large genomic deletions as determinants of BCG attenuation, small genetic changes clearly alter mycobacterial phenotype (14,22,25) and may play important roles in virulence.…”

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confidence: 99%

Contribution of L‐Alanine Dehydrogenase to In Vivo Persistence and Protective Efficacy of the BCG Vaccine

Scandurra

Ryan

Pinto

et al. 2006

Microbiology and Immunology

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The tuberculosis (TB) vaccine strain Mycobacterium bovis BCG is unable to utilise alanine and this deficiency is thought to inhibit the growth of the vaccine in vivo and limit vaccine efficacy. In this report we demonstrate that L‐alanine catabolism can be conferred on BCG by introduction of the gene encoding L‐alanine dehydrogenase (Ald) of Mycobacterium tuberculosis. Restoration of Ald activity did not change the in vivo growth of BCG in macrophages or mice, and protection against aerosol M. tuberculosis infection was not altered by addition of ald to the BCG vaccine. These results demonstrate that the inability to utilise L‐alanine is not a contributing factor to the attenuated phenotype of BCG and does not influence the protective efficacy of the vaccine against TB.

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Impact of Methoxymycolic Acid Production by Mycobacterium bovis BCG Vaccines

Cited by 29 publications

References 31 publications

BCG Vaccines: Their mechanisms of attenuation and impact on safety and protective efficacy

BCG Vaccines: Their mechanisms of attenuation and impact on safety and protective efficacy

Evolution of the Mycobacterial SigK Regulon

Contribution of L‐Alanine Dehydrogenase to In Vivo Persistence and Protective Efficacy of the BCG Vaccine

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