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Tuberculosis, a human infectious disease caused by  Mycobacterium tuberculosis  ( M.tb ), is still a major cause of morbidity and mortality worldwide. The success of  M.tb  as a pathogen relies mainly on its ability to divert the host innate immune responses. One way by which  M.tb  maintains a persistent infection in a “silent” granuloma is to inhibit inflammation and induce an immunoregulatory phenotype in host macrophages (MΦs). However,  M.tb  effectors governing the switch of MΦs from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype remain to be determined. The  E arly  S ecreted  A ntigenic  T arget 6 kDa or ESAT-6, has been implicated in the virulence and pathogenesis of tuberculosis. Here, we investigated roles of ESAT-6 in MΦ differentiation and polarization. We found that treatment of human monocytes with ESAT-6 did not interfere with differentiation of M1 MΦs. However, ESAT-6 promoted differentiation of M0 and M2 MΦs toward the M1 phenotype, as indicated by secretion of pro-inflammatory cytokines IL-6, IL-12, and TNF-α, and induction of a typical M1 transcriptional signature. Interestingly, we found that ESAT-6 switched terminal full activation of M1 polarized MΦs to the M2 phenotype. Indeed, in the pro-inflammatory M1 MΦs, ESAT-6 was able to inhibit IL-12 and TNF-α secretion and stimulate that of IL-10. Moreover, gene expression profiling of these cells showed that ESAT-6 induced downregulation of M1 MΦ cell surface molecules  CD80  and  CD86 , transcription factors  IRF5  and  c-MAF , cytokines  IL-12, IL-10 , and  IL-6 , as well as chemokines  CXCL10  and  CXCL1 . Overall, our findings suggest ESAT-6 as being one of the effectors used by  M.tb  to induce the pro-inflammatory M1 phenotype at the primo-infection; a prerequisite step to promote granuloma formation and subsequently drive the phenotype switch of MΦ polarization from M1 to M2 at a later stage of the infection. Our study improves current knowledge regarding mechanisms of virulence of  M.tb  and may be helpful to develop novel tools targeting ESAT-6 for a better and more efficient treatment of tuberculosis.

frontiers in cellular and infection microbiology

Mycobacterium tuberculosis Virulent Factor ESAT-6 Drives Macrophage Differentiation Toward the Pro-inflammatory M1 Phenotype and Subsequently Switches It to the Anti-inflammatory M2 Phenotype