Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer

Singh, Alok Kumar; Praharaj, Monali; Lombardo, Kara; Yoshida, Takahiro; Matoso, Andrés; Baras, Alexander S.; Zhao, Liang; Srikrishna, Geetha; Huang, Joy; Prasad, P. H.; Powell, Jonathan D.; Kates, Max; McConkey, David J.; Pardoll, Drew M.; Bishai, William R.; Bivalacqua, Trinity J.

doi:10.1038/s41467-022-28509-z

Cited by 44 publications

(46 citation statements)

References 62 publications

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“…However, the results showed that the transcription levels of IFN-g, IL-2 and IL-10 in the lung were no changes after M. tuberculosis infection in the lung of all groups (Figure 2F). These data suggested that rBCG-DisA immunization induced higher level of trained immunity in the lung, and were in line with such recombinant BCG that could trigger proinflammatory cytokine responses in vitro of BMDMs and macrophage cell line (31,32).…”

Section: Rbcg-disa Elicited Greater Inflammatory Cytokines In the Lun...supporting

confidence: 66%

Cyclic di-AMP as endogenous adjuvant enhanced BCG-induced trained immunity and protection against Mycobacterium tuberculosis in mice

Ning

Kang

et al. 2022

Front. Immunol.

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Bacillus Calmette-Guérin (BCG) is a licensed prophylactic vaccine against tuberculosis (TB). Current TB vaccine efforts focus on improving BCG effects through recombination or genetic attenuation and/or boost with different vaccines. Recent years, it was revealed that BCG could elicit non-specific heterogeneous protection against other pathogens such as viruses through a process termed trained immunity. Previously, we constructed a recombinant BCG (rBCG-DisA) with elevated c-di-AMP as endogenous adjuvant by overexpressing di-adenylate cyclase of Mycobacterium tuberculosis DisA, and found that rBCG-DisA induced enhanced immune responses by subcutaneous route in mice after M. tuberculosis infection. In this study, splenocytes from rBCG-DisA immunized mice by intravenous route (i.v) elicited greater proinflammatory cytokine responses to homologous and heterologous re-stimulations than BCG. After M. tuberculosis infection, rBCG-DisA immunized mice showed hallmark responses of trained immunity including potent proinflammatory cytokine responses, enhanced epigenetic changes, altered lncRNA expressions and metabolic rewiring in bone marrow cells and other tissues. Moreover, rBCG-DisA immunization induced higher levels of antibodies and T cells responses in the lung and spleen of mice after M. tuberculosis infection. It was found that rBCG-DisA resided longer than BCG in the lung of M. tuberculosis infected mice implying prolonged duration of vaccine efficacy. Then, we found that rBCG-DisA boosting could prolong survival of BCG-primed mice over 90 weeks against M. tuberculosis infection. Our findings provided in vivo experimental evidence that rBCG-DisA with c-di-AMP as endogenous adjuvant induced enhanced trained immunity and adaptive immunity. What’s more, rBCG-DisA showed promising potential in prime-boost strategy against M. tuberculosis infection in adults.

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Section: Rbcg-disa Elicited Greater Inflammatory Cytokines In the Lun...supporting

confidence: 66%

Cyclic di-AMP as endogenous adjuvant enhanced BCG-induced trained immunity and protection against Mycobacterium tuberculosis in mice

Ning

Kang

et al. 2022

Front. Immunol.

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“…Intravesical instillation of rBCG secreting certain cytokines, such as IFN-γ [ 35 ], IFN-α [ 43 ] or IL-15 [ 57 ], or various chimeric proteins in which GM-CSF is fused to cancer antigens [ 67 , 68 , 69 ], has been shown to result in prolonged survival and enhanced tumor growth suppression compared to the installation of pBCG in various mouse models of bladder cancer. Expression of bacterial toxin fragments, such as PTA [ 93 ] or increased production of c-di-AMP [ 131 ], has also improved the performance of BCG against tumor growth in murine and models.…”

Section: Discussionmentioning

confidence: 99%

“…In another study with a different rBCG::DisA strain in which disA expression is under the control of the strong hsp60 promoter, improved protection over pBCG against M. tuberculosis challenge could be demonstrated using a guinea pig model [ 130 ]. In this strain, disA expression was increased 300-fold and c-di-AMP production 15-fold compared to the parental strain [ 131 ]. This overexpression resulted in increased induction of IRF3 and ifnb expression in infected macrophages and subsequent increased levels of TNF-α, IL-6 and IL-1ß secretion [ 130 ].…”

Section: Recombinant Bcg Strains Producing Non-protein Immunomodulato...mentioning

confidence: 99%

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Recombinant BCG to Enhance Its Immunomodulatory Activities

Kowalewicz-Kulbat

Locht

2022

Vaccines

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The bacillus Calmette–Guérin (BCG) is an attenuated Mycobacterium bovis derivative that has been widely used as a live vaccine against tuberculosis for a century. In addition to its use as a tuberculosis vaccine, BCG has also been found to have utility in the prevention or treatment of unrelated diseases, including cancer. However, the protective and therapeutic efficacy of BCG against tuberculosis and other diseases is not perfect. For three decades, it has been possible to genetically modify BCG in an attempt to improve its efficacy. Various immune-modulatory molecules have been produced in recombinant BCG strains and tested for protection against tuberculosis or treatment of several cancers or inflammatory diseases. These molecules include cytokines, bacterial toxins or toxin fragments, as well as other protein and non-protein immune-modulatory molecules. The deletion of genes responsible for the immune-suppressive properties of BCG has also been explored for their effect on BCG-induced innate and adaptive immune responses. Most studies limited their investigations to the description of T cell immune responses that were modified by the genetic modifications of BCG. Some studies also reported improved protection by recombinant BCG against tuberculosis or enhanced therapeutic efficacy against various cancer forms or allergies. However, so far, these investigations have been limited to mouse models, and the prophylactic or therapeutic potential of recombinant BCG strains has not yet been illustrated in other species, including humans, with the exception of a genetically modified BCG strain that is now in late-stage clinical development as a vaccine against tuberculosis. In this review, we provide an overview of the different molecular engineering strategies adopted over the last three decades in order to enhance the immune-modulatory potential of BCG.

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“…Now, c-di-AMP has been considered a key mycobacterial pathogen-associated molecular pattern (PAMP) inducing host innate immune responses, including type I IFN response and autophagy ( Woodward et al, 2010 ; Dey et al, 2015 ; Devaux et al, 2018 ; Ning et al, 2019 ; Singh et al, 2022 ). Additionally, c-di-AMP as an adjuvant enhanced antigen-induced Th1/Th2/Th17 pattern responses ( Ebensen et al, 2011 ; Ning et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

c-di-AMP Accumulation Regulates Growth, Metabolism, and Immunogenicity of Mycobacterium smegmatis

et al. 2022

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Cyclic dimeric adenosine monophosphate (c-di-AMP) is a ubiquitous second messenger of bacteria involved in diverse physiological processes as well as host immune responses. MSMEG_2630 is a c-di-AMP phosphodiesterase (cnpB) of Mycobacterium smegmatis, which is homologous to Mycobacterium tuberculosis Rv2837c. In this study, cnpB-deleted (ΔcnpB), -complemented (ΔcnpB::C), and -overexpressed (ΔcnpB::O) strains of M. smegmatis were constructed to investigate the role of c-di-AMP in regulating mycobacterial physiology and immunogenicity. This study provides more precise evidence that elevated c-di-AMP level resulted in smaller colonies, shorter bacteria length, impaired growth, and inhibition of potassium transporter in M. smegmatis. This is the first study to report that elevated c-di-AMP level could inhibit biofilm formation and induce porphyrin accumulation in M. smegmatis by regulating associated gene expressions, which may have effects on drug resistance and virulence of mycobacterium. Moreover, the cnpB-deleted strain with an elevated c-di-AMP level could induce enhanced Th1 immune responses after M. tuberculosis infection. Further, the pathological changes and the bacteria burden in ΔcnpB group were comparable with the wild-type M. smegmatis group against M. tuberculosis venous infection in the mouse model. Our findings enhanced the understanding of the physiological role of c-di-AMP in mycobacterium, and M. smegmatis cnpB-deleted strain with elevated c-di-AMP level showed the potential for a vaccine against tuberculosis.

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Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer

Cited by 44 publications

References 62 publications

Cyclic di-AMP as endogenous adjuvant enhanced BCG-induced trained immunity and protection against Mycobacterium tuberculosis in mice

Cyclic di-AMP as endogenous adjuvant enhanced BCG-induced trained immunity and protection against Mycobacterium tuberculosis in mice

Recombinant BCG to Enhance Its Immunomodulatory Activities

c-di-AMP Accumulation Regulates Growth, Metabolism, and Immunogenicity of Mycobacterium smegmatis

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