Makram Essafi Poster 2023

Professor Makram Essafi

Institut Pasteur de Tunis, Tunisia

Activation of the Host FOXO3 during BCG vaccination confers higher protection against Mycobacterium tuberculosis

Poster Abstract

BCG failure to induce long-term protection has been endowed to its mild activation of CD8-T cell responses along with the induction of the immunosuppressive cytokine IL-10.  Enhanced apoptosis of BCG-infected macrophages potentiates dendritic cells- mediated priming of CD8T-cells, a process defined as “cross-priming”, while inhibition of IL-10 signalling, during BCG vaccination, confers higher protection against Mtb through a sustained Th1 and Th17 responses. We previously reported that apoptosis of BCG-infected macrophages relies on activation of FOXO3, a transcription factor negatively regulated by the pro-survival Akt kinase. We also found that FOXO3 inhibits IL-10 secretion in mycobacteria-infected macrophage through the direct binding to and repression of IL-10 promoter. We aim then to activate FOXO3, during BCG vaccination, as a strategy to induce a robust cellular protective immune response through the dual FOXO3-mediated effects on apoptosis and IL10 secretion. In the present study, we assessed the protective effect of the combination of BCG and the anticancer candidate MK-2206 (an Akt inhibitor/FOXO3 activator), against Mtb infection in animal model of infection. We observed that in vitro treatment with the MK-2206 activated FOXO3 leading to an enhancement of apoptosis and IL-10 abrogation in BCG-infected macrophages.

Co-administration of 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 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 

Biography

I am leading a group working on the role of host innate immune response in the establishment of efficient adaptive immune response against TB. The major aim is to uncover the host factors involved in such response to help generating tools to be used either as adjuncts for the standard treatment of TB or as adjuvants to enhance the efficacy of BCG. The data we generated led us to work on the development of better versions of BCG vaccine to prevent/treat Tuberculosis. Our approach consists of optimizing the host innate immune response (apoptosis, phagosome/cytosol translocation and IL-10 secretion) towards the establishment of an efficient CD8-mediated adaptive immune response.  A second part of our work is dedicated to study the interactions of human macrophage with Mycobacterium tuberculosis (Mtb) virulent factors, mainly ESAT-6/CFP10 complex. Our findings strongly suggest ESAT-6 as being one of the effectors used by M. tuberculosis to drive the switch of macrophages polarization from M1 to M2 phenotype. Our study also improves the current knowledge regarding mechanisms of virulence of M. tuberculosis and may be helpful to develop novel tools targeting ESAT-6 for a better and more efficient treatment of tuberculosis. The group is also working in collaboration with local and international teams to develop novel tools for TB diagnosis