A Replication-Limited Recombinant
            <i>Mycobacterium bovis</i>
            BCG Vaccine against Tuberculosis Designed for Human Immunodeficiency Virus-Positive Persons Is Safer and More Efficacious than BCG

Tullius, Michael V.; Harth, Günter; Masleša-Galić, Saša; Dillon, Barbara Jane; Horwitz, Marcus A.

doi:10.1128/iai.00434-08

Cited by 77 publications

(76 citation statements)

References 49 publications

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“…These experiments did not evaluate total cellular uptake of transferrin-bound iron into the cells, which might have occurred by the alternate mechanism described in this study. Supporting the existence of siderophoreindependent mechanisms are reports of the recombinant BCG(mbtB)30 strain that was unable to synthesize both mycobactin and carboxymycobactin yet survived in vivo and was able to acquire transferrin iron 14 .…”

Section: Discussionmentioning

confidence: 97%

“…However, 24 h post infection, the mutant strain displayed lower iron levels than the wild type. Survival of the rBCG(mbtB)30 strain also appeared to be independent of siderophores at the early stages of infection in in vivo studies using SCID mice 14 . This suggests that during establishment of infection a rapid siderophore-independent uptake mechanism for Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, it is also known that M.tb and M. bovis BCG strains incapable of synthesizing siderophores, survive intracellularly 5,14 . Within the first hour of infection, the phagosomal vacuole containing M.tb H37RvO1A siderophore knockout strain acquired more transferrin iron than the wild-type M.tb H37Rv strain 5 .…”

Section: Discussionmentioning

confidence: 99%

“…Another recent study demonstrates that the recombinant BCG(mbtB)30 strain which is unable to synthesize both mycobactin and carboxymycobactin retains the ability to multiply and survive within macrophages over the initial days of infection 14 . The importance of transferrin in mycobacterial iron acquisition is also evident from studies demonstrating that intraphagosomal M.tb siderophore knockout strains retained the ability to recruit and acquire iron by utilizing transferrin 5,14,15 . Other studies have demonstrated that ironsaturated transferrin promotes the replication of M. avium within the phagosome 15 .…”

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confidence: 99%

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Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin

et al. 2014

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Mycobacterium tuberculosis (M.tb), which requires iron for survival, acquires this element by synthesizing iron-binding molecules known as siderophores and by recruiting a host iron-transport protein, transferrin, to the phagosome. The siderophores extract iron from transferrin and transport it into the bacterium. Here we describe an additional mechanism for iron acquisition, consisting of an M.tb protein that drives transport of human holo-transferrin into M.tb cells. The pathogenic strain M.tb H37Rv expresses several proteins that can bind human holo-transferrin. One of these proteins is the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH, Rv1436), which is present on the surface of M.tb and its relative Mycobacterium smegmatis. Overexpression of GAPDH results in increased transferrin binding to M.tb cells and iron uptake. Human transferrin is internalized across the mycobacterial cell wall in a GAPDH-dependent manner within infected macrophages.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin

et al. 2014

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“…Therefore, the same, completely safe vaccine would have to be used in all vaccinees. Such a vaccine will probably be a nonviable antigenic preparation with an adjuvant, or a stable, highly attenuated, nonreplicating mycobacterial strain [17]. While the prevention of TB in HIV-positive individuals is obviously a high priority for public-health officials worldwide, it would be a shame if the HIV-negative segment of the population was denied access to a living attenuated vaccine, which may well prove to be more effective.…”

Section: One Size Fits Allmentioning

confidence: 99%

TB vaccines: the paradigms they are a-shifting

McMurray

2009

Expert Review of Vaccines

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"The urgency to license a new TB vaccine has driven a worldwide effort over the past 20 years involving basic scientists, public and private funding agencies, regulatory bodies, and disease control experts in high-burden countries."Traditional roadblocks to effective TB control (e.g., lack of attention to the disease, lack of resources, antiquated diagnostic tests, lack of patient compliance with therapy and a huge reservoir of persistently infected individuals) have been compounded by the terrible synergy between TB and HIV, and the development of almost untreatable multi-and extensively drug-resistant strains of Mycobacterium tuberculosis [1]. Case-finding and chemotherapy employing the Directly Observed Treatment, Short-course strategy, and several promising new TB drugs currently in the pipeline, will undoubtedly continue to have a significant impact on TB incidence [2,3]. However, it is clear that an effective vaccine is essential if TB is to be controlled as rapidly as possible [4][5][6]. The urgency to license a new TB vaccine has driven a worldwide effort over the past 20 years involving basic scientists, public and private funding agencies, regulatory bodies, and disease control experts in highburden countries [7]. That effort has been shaped at various stages by several paradigms that reflected the current understanding of the type of vaccine that would be needed, the manner in which vaccines should be evaluated for efficacy in animal models, the process by which preclinical development of vaccines would occur, the design of clinical trials, and the public and private organizations that would participate in the process. Almost without exception, those paradigms have shifted as the understanding of vaccine-induced protection has improved, an appreciation for the biological relevance of certain animal models of TB has grown, new strategies for organizing and funding preclinical development and human trials have emerged, and the realities of testing and using TB vaccines in diverse high-burden populations have become apparent. Variety is the spice of lifeIn general, the induction of protective cell-mediated immunity is much more challenging than inducing a protective antibody response, a fact which has complicated the search for a better TB vaccine. The current vaccine, bacillus CalmetteGuérin (BCG), is a living, attenuated strain (actually several different strains) of Mycobacterium bovis, which has served as a model for new TB vaccines and a gold standard for their evaluation in animal models [8]. BCG has many characteristics that recommend it as a platform for new TB vaccines, and several of the promising new vaccines utilize recombinant BCG strains overexpressing the genes for several mycobacterial antigens [9,10]. However, the fact that BCG does not seem to protect against adult pulmonary TB in some high-burden settings has stimulated the search for other types of TB vaccines. The traditional approach of using purified components of the bacterium together with an effective adjuvant has been modernize...

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Zinc‐Dependent Metalloprotease‐1 (Zmp1)

Ferraris

Rizzi

2004

Encyclopedia of Inorganic and Bioinorganic Chemistry

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M13 endopeptidases are single‐pass, transmembrane zinc‐metallopeptidases responsible for the regulation of the biological activity of many hormones and peptides in humans and are involved in many important processes such as blood pressure regulation (neprilysin or NEP), cardiovascular development ( endothelin converting enzyme‐1 or ECE‐1 ), and prevention of hemolytic reaction ( KELL ) and phosphate homeostasis ( PHEX ). Zmp1 is a soluble enzyme member of the M13 endopetidases family, which plays a key role in Mycobacterium tuberculosis pathogenicity through a still to be elucidated mechanism that likely initiates on enzyme secretion.

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A Replication-Limited Recombinant Mycobacterium bovis BCG Vaccine against Tuberculosis Designed for Human Immunodeficiency Virus-Positive Persons Is Safer and More Efficacious than BCG

Abstract: Tuberculosis is the leading cause of death in AIDS patients

Cited by 77 publications

References 49 publications

Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin

Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin

TB vaccines: the paradigms they are a-shifting

Zinc‐Dependent Metalloprotease‐1 (Zmp1)

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