The live Mycobacterium tuberculosis phoP mutant strain is more attenuated than BCG and confers protective immunity against tuberculosis in mice and guinea pigs

Martín, Carlos; Williams, Ann; Hernández-Pando, Rogelio; Cardona, Père-Joan; Gormley, Eamonn; Bordat, Yann; Soto, Carlos Y.; Clark, Simon; Hatch, Graham; Aguilar, Diana; Ausina, V.; Gicquel, Brigitte

doi:10.1016/j.vaccine.2006.03.017

Cited by 211 publications

(165 citation statements)

References 38 publications

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“…phoP is a transcription regulator, therefore its mutation determines lack of expression of several genes, including virulence factors, such as ESAT6 [82]. Although SO2 seemed to be immunogenic and protective against TB in animal models [82,83], it failed to satisfy the Geneva consensus requirements for progressing new vaccines into clinical trials [81]. …”

Section: Resultsmentioning

confidence: 99%

Vaccine against tuberculosis: what’s new?

et al. 2014

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Backgroundone of the World Health Organization Millennium Development Goal is to reduce tuberculosis incidence by 2015. However, more of 8.5 million tuberculosis cases have been reported in 2011, with an increase of multidrug-resistant strains. Therefore, the World Health Organization target cannot be reach without the help of a vaccine able to limit the spread of tuberculosis. Nowadays, bacille Calmette-Guérin is the only vaccine available against tuberculosis. It prevents against meningeal and disseminated tuberculosis in children, but its effectiveness against pulmonary form in adolescents and adults is argued.Methoda systematic review was performed by searches of Pubmed, references of the relevant articles and Aeras and ClinicalTrial.gov websites.Results100 articles were included in this review. Three viral vectored booster vaccines, five protein adjuvant booster vaccines, two priming vaccines and two therapeutic vaccines have been analyzed.ConclusionsSeveral vaccines are in the pipeline, but further studies on basic research, clinical trial and mass vaccination campaigns are needed to achieve the TB eradication target by 2050.

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Section: Resultsmentioning

confidence: 99%

Vaccine against tuberculosis: what’s new?

et al. 2014

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“…The PhoP-PhoR system has been implicated in the M. tuberculosis growth and survival in animal and cellular models because a phoP knock-out mutant of M. tuberculosis showed significant growth attenuation in both macrophages and in mice (4 -7). Growing evidence indicates that PhoP regulates biosynthesis of sulfolipids (SL), diacyltrehaloses (DATs), and polyacyltrehaloses (PATs), and the absence of these complex lipid molecules in the phoP mutant is a major reason for the attenuated growth of the bacilli in a mouse model (5,6,8,9). More recent studies suggest that PhoP, in addition to complex lipid biosynthesis, impacts numerous aspects of M. tuberculosis physiology, including early and enduring hypoxic responses (10), regulation of ESAT-6 secretion, specific T-cell recognition during virulence regulation of the bacilli (10 -12), and pH sensing during intracellular adaptation (13).…”

Section: Mycobacterium Tuberculosismentioning

confidence: 99%

Phosphorylation of PhoP Protein Plays Direct Regulatory Role in Lipid Biosynthesis of Mycobacterium tuberculosis

Goyal¹,

Das²,

Singh³

et al. 2011

Journal of Biological Chemistry

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Background:PhoP is global regulator of Mycobacterium tuberculosis physiology. However, the role of phosphorylation of PhoP remains unknown. Results: PhoP activates complex lipid biosynthesis only upon phosphorylation. Conclusion: PhoP regulates lipid biosynthesis by a phosphorylation-dependent mechanism to contribute to morphology of the bacilli. Significance: This study sheds light on the unexplored role of phosphorylation of PhoP in regulating biosynthesis of lipids unique to M. tuberculosis.

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“…61 The PhoR protein is a transmembrane histidine kinase that transmits signals from the environment. Autophosphorylation of PhoR is followed by transfer of the phosphoryl group to PhoP, a response regulator that mediates expression of multiple genes, 62 including genes for the biosynthesis of trehalose-containing cell wall lipids [63][64][65] and ESX-1 secretion. 66 A role for phoP in virulence of the M. tb complex was first suggested during a severe nosocomial outbreak of multidrug resistant TB in humans in Spain.…”

Section: Correlation With Residual Virulence and Reactogenicitymentioning

confidence: 99%

“…63 Collectively, these studies have demonstrated that the PhoP-PhoR system, particularly PhoP, plays an essential role in M. tb virulence. 62,65,66,69 Considering its prominent role in virulence, it may not be surprising that BCG strains exhibit a number of genetic polymorphisms in the phoP-phoR locus. 20 A frame-shift mutation within the phoP gene of BCG-Prague 20 eliminates the majority of C-terminal DNA binding domain, and makes this strain a natural phoP mutant.…”

Section: Correlation With Residual Virulence and Reactogenicitymentioning

confidence: 99%

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

Liu

Tran²,

Leung³

et al. 2009

Human Vaccines

125

117

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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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The live Mycobacterium tuberculosis phoP mutant strain is more attenuated than BCG and confers protective immunity against tuberculosis in mice and guinea pigs

Cited by 211 publications

References 38 publications

Vaccine against tuberculosis: what’s new?

Vaccine against tuberculosis: what’s new?

Phosphorylation of PhoP Protein Plays Direct Regulatory Role in Lipid Biosynthesis of Mycobacterium tuberculosis

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

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