In:
Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-5-27)
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
1664-3224
DOI:
10.3389/fimmu.2021.645962
DOI:
10.3389/fimmu.2021.645962.s001
Sprache:
Unbekannt
Verlag:
Frontiers Media SA
Publikationsdatum:
2021
ZDB Id:
2606827-8
