Current efforts and future prospects in the development of live mycobacteria as vaccines

Ng, Tony W.; Saavedra-Ávila, Noemí Alejandra; Kennedy, Steven C.; Carreño, Leandro J.; Porcelli, Steven A.

doi:10.1586/14760584.2015.1089175

Cited by 14 publications

(16 citation statements)

References 133 publications

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“…Exploring these molecular mechanisms should help in the development of new compounds to either stimulate autophagy in the context of host-directed therapy against tuberculosis [5] or to limit detrimental autophagy in some other pathological contexts [63,64]. A deeper understanding of the multiple roles of autophagy in Mtb infection is warranted to discover important clues for the development of autophagy-based vaccines against and therapies for tuberculosis [65,66]. [1].…”

Section: Discussionmentioning

confidence: 99%

The Lipid Virulence Factors of Mycobacterium tuberculosis Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages

Bah

Sanicas

Nigou

et al. 2020

Cells

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Autophagy is an important innate immune defense mechanism that controls Mycobacterium tuberculosis (Mtb) growth inside macrophages. Autophagy machinery targets Mtb-containing phagosomes via xenophagy after damage to the phagosomal membrane due to the Type VII secretion system Esx-1 or via LC3-associated phagocytosis without phagosomal damage. Conversely, Mtb restricts autophagy-related pathways via the production of various bacterial protein factors. Although bacterial lipids are known to play strategic functions in Mtb pathogenesis, their role in autophagy manipulation remains largely unexplored. Here, we report that the lipid virulence factors sulfoglycolipids (SLs) and phthiocerol dimycocerosates (DIMs) control autophagy-related pathways through distinct mechanisms in human macrophages. Using knock-out and knock-in mutants of Mtb and Mycobacterium bovis BCG (Bacille Calmette Guerin) and purified lipids, we found that (i) Mtb mutants with DIM and SL deficiencies promoted functional autophagy via an MyD88-dependent and phagosomal damage-independent pathway in human macrophages; (ii) SLs limited this pathway by acting as TLR2 antagonists; (iii) DIMs prevented phagosomal damage-independent autophagy while promoting Esx-1-dependent xenophagy; (iv) and DIMs, but not SLs, limited the acidification of LC3-positive Mtb compartments. In total, our study reveals an unexpected and intricate role for Mtb lipid virulence factors in controlling autophagy-related pathways in human macrophages, thus providing further insight into the autophagy manipulation tactics deployed by intracellular bacterial pathogens.

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Section: Discussionmentioning

confidence: 99%

The Lipid Virulence Factors of Mycobacterium tuberculosis Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages

Bah

Sanicas

Nigou

et al. 2020

Cells

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“…Numerous attempts to obtain an M. tuberculosis vaccine that demonstrates enhanced protection over BCG, durability, and safety have been made (7). Administration of additional doses of BCG did not boost the protection afforded by BCG (8).…”

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confidence: 99%

Identification of Mycobacterial RplJ/L10 and RpsA/S1 Proteins as Novel Targets for CD4⁺T Cells

et al. 2017

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Tuberculosis (TB) due to Mycobacterium tuberculosis remains a major global infectious disease problem, and a more efficacious vaccine is urgently needed for the control and prevention of disease caused by this organism. We previously reported that a genetically modified strain of Mycobacterium smegmatis called IKEPLUS is a promising TB vaccine candidate. Since protective immunity induced by IKEPLUS is dependent on antigen-specific CD4 ϩ T cell memory, we hypothesized that the specificity of the CD4 ϩ T cell response was a critical feature of this protection. Using in vitro assays of interferon gamma production (enzyme-linked immunosorbent spot [ELISPOT] assays) by splenocytes from IKEPLUS-immunized C57BL/6J mice, we identified an immunogenic peptide within the mycobacterial ribosomal large subunit protein RplJ, encoded by the Rv0651 gene. In a complementary approach, we generated major histocompatibility complex (MHC) class II-restricted T cell hybridomas from IKEPLUS-immunized mice. Screening of these T cell hybridomas against IKE-PLUS and ribosomes enriched from IKEPLUS suggested that the CD4 ϩ T cell response in IKEPLUS-immunized mice was dominated by the recognition of multiple components of the mycobacterial ribosome. Importantly, CD4 ϩ T cells specific for mycobacterial ribosomes accumulate to significant levels in the lungs of IKEPLUSimmunized mice following aerosol challenge with virulent M. tuberculosis, consistent with a role for these T cells in protective host immunity in TB. The identification of CD4 ϩ T cell responses to defined ribosomal protein epitopes expands the range of antigenic targets for adaptive immune responses to M. tuberculosis and may help to inform the design of more effective vaccines against tuberculosis.

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“…Ongoing work seeks to optimize the design of synthetic αGC analogs and the methods for their administration to optimize the antitumor effects of Lm‐based vaccines. Incorporation of glycolipids into other bacterial vectors, specifically in Mycobacterium bovis bacillus Calmette–Guérin (BCG), has also been studied to improve the activation of iNKT cells and favor a Th1 profile that could be beneficial for cancer immunotherapy 39 , 121 …”

Section: Live Bacteria As αGalcer Delivery Vectorsmentioning

confidence: 99%

“…Incorporation of glycolipids into other bacterial vectors, specifically in Mycobacterium bovis bacillus Calmette-Guérin (BCG), has also been studied to improve the activation of iNKT cells and favor a Th1 profile that could be beneficial for cancer immunotherapy. 39,121 USE OF SYNTHETIC αGALCER GLYCOLIPIDS AS VACCINE ADJUVANTS In addition to their potential applications for cancer immunotherapy, several αGalCer glycolipids have also been used effectively as vaccine adjuvants for prevention of infections in mouse models. 25,[57][58][59][122][123][124][125][126][127] Several experimental vaccines, including examples targeting malaria, tuberculosis, influenza and HIV, have been shown to give improved protective immunity when administered with KRN7000.…”

Section: Cell-based Therapy Using αGalcer-pulsed Dcsmentioning

confidence: 99%

Synthetic glycolipid activators of natural killer T cells as immunotherapeutic agents

2016

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Certain types of glycolipids have been found to have remarkable immunomodulatory properties as a result of their ability to activate specific T lymphocyte populations with an extremely wide range of immune effector properties. The most extensively studied glycolipid reactive T cells are known as invariant natural killer T (iNKT) cells. The antigen receptors of these cells specifically recognize certain glycolipids, most notably glycosphingolipids with α-anomeric monosaccharides, presented by the major histocompatibility complex class I-like molecule CD1d. Once activated, iNKT cells can secrete a very diverse array of pro- and anti-inflammatory cytokines to modulate innate and adaptive immune responses. Thus, glycolipid-mediated activation of iNKT cells has been explored for immunotherapy in a variety of disease states, including cancer and a range of infections. In this review, we discuss the design of synthetic glycolipid activators for iNKT cells, their impact on adaptive immune responses and their use to modulate iNKT cell responses to improve immunity against infections and cancer. Current challenges in translating results from preclinical animal studies to humans are also discussed.

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Current efforts and future prospects in the development of live mycobacteria as vaccines

Cited by 14 publications

References 133 publications

The Lipid Virulence Factors of Mycobacterium tuberculosis Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages

The Lipid Virulence Factors of Mycobacterium tuberculosis Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages

Identification of Mycobacterial RplJ/L10 and RpsA/S1 Proteins as Novel Targets for CD4⁺T Cells

Synthetic glycolipid activators of natural killer T cells as immunotherapeutic agents

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Current efforts and future prospects in the development of live mycobacteria as vaccines

Cited by 14 publications

References 133 publications

The Lipid Virulence Factors of Mycobacterium tuberculosis Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages

The Lipid Virulence Factors of Mycobacterium tuberculosis Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages

Identification of Mycobacterial RplJ/L10 and RpsA/S1 Proteins as Novel Targets for CD4+T Cells

Synthetic glycolipid activators of natural killer T cells as immunotherapeutic agents

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Identification of Mycobacterial RplJ/L10 and RpsA/S1 Proteins as Novel Targets for CD4⁺T Cells