AUTHOR=Refai Amira , Gritli Sami , Barbouche Mohamed-Ridha , Essafi Makram 

TITLE=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

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=8

YEAR=2018

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2018.00327

DOI=10.3389/fcimb.2018.00327

ISSN=2235-2988

ABSTRACT=<p>Tuberculosis, a human infectious disease caused by <italic>Mycobacterium tuberculosis</italic> (<italic>M.tb</italic>), is still a major cause of morbidity and mortality worldwide. The success of <italic>M.tb</italic> as a pathogen relies mainly on its ability to divert the host innate immune responses. One way by which <italic>M.tb</italic> maintains a persistent infection in a “silent” granuloma is to inhibit inflammation and induce an immunoregulatory phenotype in host macrophages (MΦs). However, <italic>M.tb</italic> effectors governing the switch of MΦs from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype remain to be determined. The <italic>E</italic>arly <italic>S</italic>ecreted <italic>A</italic>ntigenic <italic>T</italic>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 <italic>CD80</italic> and <italic>CD86</italic>, transcription factors <italic>IRF5</italic> and <italic>c-MAF</italic>, cytokines <italic>IL-12, IL-10</italic>, and <italic>IL-6</italic>, as well as chemokines <italic>CXCL10</italic> and <italic>CXCL1</italic>. Overall, our findings suggest ESAT-6 as being one of the effectors used by <italic>M.tb</italic> 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 <italic>M.tb</italic> and may be helpful to develop novel tools targeting ESAT-6 for a better and more efficient treatment of tuberculosis.</p>