Deletion of
 nuoG
 from the Vaccine Candidate Mycobacterium bovis BCG Δ
 ureC
 ::
 hly
 Improves Protection against Tuberculosis

Gengenbacher, Martin; Nieuwenhuizen, Natalie E.; Vogelzang, Alexis; Zheng, Tiansheng; Kaiser, Peggy; Schuerer, Stefanie; Lazar, Doris; Wagner, Ina; Mollenkopf, Hans-Joachim; Kaufmann, Stefan H. E.

doi:10.1128/mbio.00679-16

Cited by 69 publications

(66 citation statements)

References 42 publications

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“…Recently, T FH cells have emerged as important mediators in the development of BCG immunity. While studying the BCG ΔureC∷hly vaccine, it was discovered that the superior efficacy behind this vaccine correlates with higher levels of central memory T cells and T FH cells (170, 171). Though promising, further research will reveal the importance of T FH in the context of mycobacterial immunity.…”

Section: Adaptive Immune Responses To Bcg Vaccinationmentioning

confidence: 99%

Immune Responses to Bacillus Calmette–Guérin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?

2017

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Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), is the current leading cause of death due to a single infectious organism. Although curable, the broad emergence of multi-, extensive-, extreme-, and total-drug resistant strains of M.tb has hindered eradication efforts of this pathogen. Furthermore, computational models predict a quarter of the world’s population is infected with M.tb in a latent state, effectively serving as the largest reservoir for any human pathogen with the ability to cause significant morbidity and mortality. The World Health Organization has prioritized new strategies for improved vaccination programs; however, the lack of understanding of mycobacterial immunity has made it difficult to develop new successful vaccines. Currently, Mycobacterium bovis bacillus Calmette–Guérin (BCG) is the only vaccine approved for use to prevent TB. BCG is highly efficacious at preventing meningeal and miliary TB, but is at best 60% effective against the development of pulmonary TB in adults and wanes as we age. In this review, we provide a detailed summary on the innate immune response of macrophages, dendritic cells, and neutrophils in response to BCG vaccination. Additionally, we discuss adaptive immune responses generated by BCG vaccination, emphasizing their specific contributions to mycobacterial immunity. The success of future vaccines against TB will directly depend on our understanding of mycobacterial immunity.

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Section: Adaptive Immune Responses To Bcg Vaccinationmentioning

confidence: 99%

Immune Responses to Bacillus Calmette–Guérin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?

2017

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“…Dying cells are one major source of antigens for crosspresentation, and L. monocytogenes induces a variety of host cell death pathways, including apoptosis, necrosis, and pyroptosis, both directly in infected cells and in uninfected bystanders (6)(7)(8)(9). In other live attenuated vaccine platforms, such as Mycobacterium bovis BCG, modulation of host cell death has been proposed as a means to increase the efficacy of this vaccine (10). However, how activation of cell death by L.…”

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confidence: 99%

“…Furthermore, modulation of activation of cell death in live attenuated vaccine platforms has recently been proposed as a mechanism to improve the efficacy of the BCG vaccine (10). To test the hypothesis that activation of cell death during infection influences the generation of adaptive immune responses, we engineered strains of L. monocytogenes to preferentially activate pyroptosis, necrosis, or apoptosis, all forms of cell death that L. monocytogenes induces throughout infection (Fig.…”

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confidence: 99%

Listeria monocytogenes-Induced Cell Death Inhibits the Generation of Cell-Mediated Immunity

Theisen

Sauer

2017

Infect Immun

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The influence of cell death on adaptive immunity has been studied for decades. Despite these efforts, the intricacies of how various cell death pathways shape immune responses in the context of infection remain unclear, particularly with regard to more recently discovered pathways such as pyroptosis. The emergence of Listeria monocytogenes as a promising immunotherapeutic platform demands a thorough understanding of how cell death induced in the context of infection influences the generation of CD8 ϩ T-cell-mediated immune responses. To begin to address this question, we designed strains of L. monocytogenes that robustly activate necrosis, apoptosis, or pyroptosis. We hypothesized that proinflammatory cell death such as necrosis would be proimmunogenic while apoptosis would be detrimental, as has previously been reported in the context of sterile cell death. Surprisingly, we found that the activation of any host cell death in the context of L. monocytogenes infection inhibited the generation of protective immunity and specifically the activation of antigen-specific CD8 ϩ T cells. Importantly, the mechanism of attenuation was unique for each type of cell death, ranging from deficits in costimulation in the context of necrosis to a suboptimal inflammatory milieu in the case of pyroptosis. Our results suggest that cell death in the context of infection is different from sterileenvironment-induced cell death and that inhibition of cell death or its downstream consequences is necessary for developing effective cell-mediated immune responses using L. monocytogenes-based immunotherapeutic platforms. KEYWORDS Listeria monocytogenes, apoptosis, cell death, immunotherapy, inflammasomeL isteria monocytogenes is a Gram-positive, genetically tractable pathogen that stimulates a robust CD8 ϩ T-cell response capable of breaking self-tolerance. These properties combine to make L. monocytogenes a promising cancer immunotherapeutic platform (1). The use of attenuated L. monocytogenes has done well in clinical trials (2); however, the mechanism by which L. monocytogenes stimulates robust cell-mediated immunity remains largely unknown. Throughout the course of infection, L. monocytogenes triggers a variety of innate immune responses, including Toll-like receptor (TLR) signaling and type I interferons (IFNs), that are hypothesized to be required for the development of a host protective immune response (reviewed in reference 3). Further, cross-priming from CD8␣ dendritic cells (DCs) is important to induce L. monocytogenesstimulated immunity (4, 5). Dying cells are one major source of antigens for crosspresentation, and L. monocytogenes induces a variety of host cell death pathways, including apoptosis, necrosis, and pyroptosis, both directly in infected cells and in uninfected bystanders (6-9). In other live attenuated vaccine platforms, such as Mycobacterium bovis BCG, modulation of host cell death has been proposed as a means to increase the efficacy of this vaccine (10). However, how activation of cell death by L.

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“…This TB vaccine has been genetically manipulated to permit its escape from the endosome, resulting in cytosolic antigen processing [33][34][35]. In preclinical studies, VPM1002 vaccine has demonstrated significant protective efficacy [36][37][38][39]. Currently, studies on this vaccine are underway in South Africa to evaluate it in efficacy trials aimed to prevent TB in HIV-exposed and non-HIV-exposed new-borns [40].…”

Section: Inactivated Whole-cell Mycobacterial Vaccinesmentioning

confidence: 99%

The current status of bacillus Calmette‐Guérin vaccine protective efficacy

Méndez-Samperio

2019

vacres

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Deletion of nuoG from the Vaccine Candidate Mycobacterium bovis BCG Δ ureC :: hly Improves Protection against Tuberculosis

Cited by 69 publications

References 42 publications

Immune Responses to Bacillus Calmette–Guérin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?

Immune Responses to Bacillus Calmette–Guérin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?

Listeria monocytogenes-Induced Cell Death Inhibits the Generation of Cell-Mediated Immunity

The current status of bacillus Calmette‐Guérin vaccine protective efficacy

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