Co-Administration of Anticancer Candidate MK-2206 Enhances the Efficacy of BCG Vaccine Against Mycobacterium tuberculosis in Mice and Guinea Pigs
| Autor: | Tannu Priya Gosain, Ramandeep Singh, Saurabh Chugh, Rania Bouzeyen, Mohamed-Ridha Barbouche, Meriam Haoues, Kanury V S Rao, Makram Essafi |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
T-Lymphocytes
Guinea Pigs Immunology Antigen-Presenting Cells Priming (immunology) Biology Phagolysosome Microbiology Mice Immunity Animals Immunology and Allergy Secretion Akt inhibitor Protein kinase B innate immunity Cells Cultured BCG vaccine Original Research Innate immune system Macrophages Forkhead Box Protein O3 apoptosis RC581-607 tuberculosis Immunologic diseases. Allergy Heterocyclic Compounds 3-Ring Immunologic Memory CD8 |
| Zdroj: | Frontiers in Immunology, Vol 12 (2021) Frontiers in Immunology |
| ISSN: | 1664-3224 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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