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

• Published in: Frontiers in cellular and infection microbiology 2018-09, Vol.8, p.327
• Main Authors: Refai, Amira, Gritli, Sami, Barbouche, Mohamed-Ridha, Essafi, Makram
• Format: Article
• Language: English
• Subjects: Antigens, Bacterial - immunology; Antigens, Bacterial - metabolism; Bacterial Proteins - immunology; Bacterial Proteins - metabolism; Cell Differentiation; Cells, Cultured; Cellular and Infection Microbiology; Cytokines - analysis; ESAT-6; Gene Expression Profiling; Host-Pathogen Interactions; Humans; Immune Evasion; Immune Tolerance; Life Sciences; M. tuberculosis; macrophages; Macrophages - drug effects; Macrophages - immunology; Microbiology and Parasitology; Phenotype; polarization; tuberculosis; Virulence Factors - immunology; Virulence Factors - metabolism
• ISSN: 2235-2988; 2235-2988
• DOI: 10.3389/fcimb.2018.00327

Tuberculosis, a human infectious disease caused by ( ), is still a major cause of morbidity and mortality worldwide. The success of as a pathogen relies mainly on its ability to divert the host innate immune responses. One way by which maintains a persistent infection in a "silent" granuloma is to inhibit inflammation and induce an immunoregulatory phenotype in host macrophages (MΦs). However, effectors governing the switch of MΦs from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype remain to be determined. The arly ecreted ntigenic 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 and , transcription factors and , cytokines , and , as well as chemokines and . Overall, our findings suggest ESAT-6 as being one of the effectors used by 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 and may be helpful to develop novel tools targeting ESAT-6 for a better and more efficient treatment of tuberculosis.