Figure 6.

ESAT-6 drives host macrophage differentiation and activation as a mechanism to first induce granuloma formation and subvert the immune response at a later stage of the infection. Resident classical M1 alveolar MΦs are the first encounters of inhaled mycobacteria. The latter ones proliferate inside the phagosome with a concomitant secretion of ESAT-6, which disseminates to nearby blood vessels and contributes to differentiation of peripheral monocytes into M1-type MΦs. The local type-1 pro-inflammatory environment along with apoptotic MΦs would further enhance recruitment of innate and adaptive immune cells, creating a bactericidal granuloma. In order to shape granuloma function to its advantage, M.tb secretes ESAT-6, which modulates MΦ pro-inflammatory M1 phenotype and induces polarization of M1 MΦs toward the immunomodulatory M2 phenotype. Part of these cells will differentiate into FMs under the action of ESAT-6. FMs represent the ideal niche for M.tb to survive in and proliferate slowly. M2 MΦs and FMs contribute to the formation of a “silent” solid granuloma with predominance of Th2 and Treg immune responses.