Co-Administration of Anticancer Candidate MK-2206 Enhances the Efficacy of BCG Vaccine Against Mycobacterium tuberculosis in Mice and Guinea Pigs
The failure of M. bovis BCG to induce long-term protection has been endowed to its inability to escape the phagolysosome, leading to mild activation of CD8+ mediated T cell response. Induction of apoptosis in host cells plays an important role in potentiating dendritic cells-mediated priming of CD8+...
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doaj-ffaa4ea1e899451aad6a467a6a8a48ab2021-05-27T04:42:25ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-05-011210.3389/fimmu.2021.645962645962Co-Administration of Anticancer Candidate MK-2206 Enhances the Efficacy of BCG Vaccine Against Mycobacterium tuberculosis in Mice and Guinea PigsRania Bouzeyen0Saurabh Chugh1Tannu Priya Gosain2Mohamed-Ridha Barbouche3Meriam Haoues4Kanury V. S. Rao5Makram Essafi6Ramandeep Singh7Institut Pasteur de Tunis, LTCII, LR11 IPT02, Tunis, TunisiaTranslational Health Science and Technology Institute, Faridabad, IndiaTranslational Health Science and Technology Institute, Faridabad, IndiaInstitut Pasteur de Tunis, LTCII, LR11 IPT02, Tunis, TunisiaInstitut Pasteur de Tunis, LTCII, LR11 IPT02, Tunis, TunisiaTranslational Health Science and Technology Institute, Faridabad, IndiaInstitut Pasteur de Tunis, LTCII, LR11 IPT02, Tunis, TunisiaTranslational Health Science and Technology Institute, Faridabad, IndiaThe failure of M. bovis BCG to induce long-term protection has been endowed to its inability to escape the phagolysosome, leading to mild activation of CD8+ mediated T cell response. Induction of apoptosis in host cells plays an important role in potentiating dendritic cells-mediated priming of CD8+ T cells, a process defined as “cross-priming.” Moreover, IL-10 secretion by infected cells has been reported to hamper BCG-induced immunity against Tuberculosis (TB). Previously, we have reported that apoptosis of BCG-infected macrophages and inhibition of IL-10 secretion is FOXO3 dependent, a transcription factor negatively regulated by the pro-survival activated threonine kinase, Akt. We speculate that FOXO3-mediated induction of apoptosis and abrogation of IL-10 secretion along with M. bovis BCG immunization might enhance the protection imparted by BCG. Here, we have assessed whether co-administration of a known anti-cancer Akt inhibitor, MK-2206, enhances the protective efficacy of M. bovis BCG in mice model of infection. We observed that in vitro MK-2206 treatment resulted in FOXO3 activation, enhanced BCG-induced apoptosis of macrophages and inhibition of IL-10 secretion. Co-administration of M. bovis BCG along with MK-2206 also increased apoptosis of antigen-presenting cells in draining lymph nodes of immunized mice. Further, MK-2206 administration improved BCG-induced CD4+ and CD8+ effector T cells responses and its ability to induce both effector and central memory T cells. Finally, we show that co-administration of MK-2206 enhanced the protection imparted by M. bovis BCG against Mtb in aerosol infected mice and guinea pigs. Taken together, we provide evidence that MK-2206-mediated activation of FOXO3 potentiates BCG-induced immunity and imparts protection against Mtb through enhanced innate immune response.https://www.frontiersin.org/articles/10.3389/fimmu.2021.645962/fullBCG vaccineAkt inhibitorinnate immunityapoptosistuberculosis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rania Bouzeyen Saurabh Chugh Tannu Priya Gosain Mohamed-Ridha Barbouche Meriam Haoues Kanury V. S. Rao Makram Essafi Ramandeep Singh |
spellingShingle |
Rania Bouzeyen Saurabh Chugh Tannu Priya Gosain Mohamed-Ridha Barbouche Meriam Haoues Kanury V. S. Rao Makram Essafi Ramandeep Singh Co-Administration of Anticancer Candidate MK-2206 Enhances the Efficacy of BCG Vaccine Against Mycobacterium tuberculosis in Mice and Guinea Pigs Frontiers in Immunology BCG vaccine Akt inhibitor innate immunity apoptosis tuberculosis |
author_facet |
Rania Bouzeyen Saurabh Chugh Tannu Priya Gosain Mohamed-Ridha Barbouche Meriam Haoues Kanury V. S. Rao Makram Essafi Ramandeep Singh |
author_sort |
Rania Bouzeyen |
title |
Co-Administration of Anticancer Candidate MK-2206 Enhances the Efficacy of BCG Vaccine Against Mycobacterium tuberculosis in Mice and Guinea Pigs |
title_short |
Co-Administration of Anticancer Candidate MK-2206 Enhances the Efficacy of BCG Vaccine Against Mycobacterium tuberculosis in Mice and Guinea Pigs |
title_full |
Co-Administration of Anticancer Candidate MK-2206 Enhances the Efficacy of BCG Vaccine Against Mycobacterium tuberculosis in Mice and Guinea Pigs |
title_fullStr |
Co-Administration of Anticancer Candidate MK-2206 Enhances the Efficacy of BCG Vaccine Against Mycobacterium tuberculosis in Mice and Guinea Pigs |
title_full_unstemmed |
Co-Administration of Anticancer Candidate MK-2206 Enhances the Efficacy of BCG Vaccine Against Mycobacterium tuberculosis in Mice and Guinea Pigs |
title_sort |
co-administration of anticancer candidate mk-2206 enhances the efficacy of bcg vaccine against mycobacterium tuberculosis in mice and guinea pigs |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2021-05-01 |
description |
The failure of M. bovis BCG to induce long-term protection has been endowed to its inability to escape the phagolysosome, leading to mild activation of CD8+ mediated T cell response. Induction of apoptosis in host cells plays an important role in potentiating dendritic cells-mediated priming of CD8+ T cells, a process defined as “cross-priming.” Moreover, IL-10 secretion by infected cells has been reported to hamper BCG-induced immunity against Tuberculosis (TB). Previously, we have reported that apoptosis of BCG-infected macrophages and inhibition of IL-10 secretion is FOXO3 dependent, a transcription factor negatively regulated by the pro-survival activated threonine kinase, Akt. We speculate that FOXO3-mediated induction of apoptosis and abrogation of IL-10 secretion along with M. bovis BCG immunization might enhance the protection imparted by BCG. Here, we have assessed whether co-administration of a known anti-cancer Akt inhibitor, MK-2206, enhances the protective efficacy of M. bovis BCG in mice model of infection. We observed that in vitro MK-2206 treatment resulted in FOXO3 activation, enhanced BCG-induced apoptosis of macrophages and inhibition of IL-10 secretion. Co-administration of M. bovis BCG along with MK-2206 also increased apoptosis of antigen-presenting cells in draining lymph nodes of immunized mice. Further, MK-2206 administration improved BCG-induced CD4+ and CD8+ effector T cells responses and its ability to induce both effector and central memory T cells. Finally, we show that co-administration of MK-2206 enhanced the protection imparted by M. bovis BCG against Mtb in aerosol infected mice and guinea pigs. Taken together, we provide evidence that MK-2206-mediated activation of FOXO3 potentiates BCG-induced immunity and imparts protection against Mtb through enhanced innate immune response. |
topic |
BCG vaccine Akt inhibitor innate immunity apoptosis tuberculosis |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2021.645962/full |
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