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Review
. 2024 Apr 3:15:1383098.
doi: 10.3389/fimmu.2024.1383098. eCollection 2024.

The role of ESAT-6 in tuberculosis immunopathology

Beatriz B S Passos  1   2   3 , Mariana Araújo-Pereira  2   3   4 , Caian L Vinhaes  2   3   4   5   6 , Eduardo P Amaral  7 , Bruno B Andrade  1   2   3   4   5
Affiliations
Review

The role of ESAT-6 in tuberculosis immunopathology

Beatriz B S Passos et al. Front Immunol. .

Abstract

Despite major global efforts to eliminate tuberculosis, which is caused by Mycobacterium tuberculosis (Mtb), this disease remains as a major plague of humanity. Several factors associated with the host and Mtb interaction favor the infection establishment and/or determine disease progression. The Early Secreted Antigenic Target 6 kDa (ESAT-6) is one of the most important and well-studied mycobacterial virulence factors. This molecule has been described to play an important role in the development of tuberculosis-associated pathology by subverting crucial components of the host immune responses. This review highlights the main effector mechanisms by which ESAT-6 modulates the immune system, directly impacting cell fate and disease progression.

Keywords: ESAT-6; cell death; immune activation; immunopathology; tuberculosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Timeline of discoveries associated with 6kDa early secretory antigenic target (ESAT-6). ESAT-6: 6kDa early secretory antigenic target; M. bovis BCG: Mycobacterium bovis Bacillus Calmette-Guérin; T-Cell: T lymphocytes; CFP-10: 10-kDa culture filtrate protein; Mtb: Mycobacterium tuberculosis; IFN-γ: Interferon-gamma; c-myc: MYC proto-oncogene; NF-K β: nuclear factor-kappa β; IGRA: Interferon-γ release assays; IL-1β: interleukin-1β; NLRP3: NLR Family Pyrin Domain Containing 3; Ca2++: calcium ion; miR-155: microRNA 155; SOCS1: suppressor of cytokine signaling 1; mTORC: mechanistic target of rapamycin kinase complex; QTF-Plus: QuantiFERON-TB Gold Plus; ROS: Reactive oxygen species; HO-1: Heme oxygenase 1; M1: Macrophages 1; M2: Macrophages 2; miR-30a-5p: microRNA 30a-5p; TNF- α: tumor necrosis factor alpha; BAX: BCL2 associated X; mTORC1: mammalian target of rapamycin complex 1.
Figure 2
Figure 2
Deciphering ESAT-6: Unraveling Protein-Mediated Pathways in Mycobacterium tuberculosis Pathogenesis. The ESAT-6 protein intricately modulates receptor activation pathways, steering cellular autophagy regulation towards cell demise and pathogenesis. Post Mtb invasion, elevated ESAT-6 triggers NLRP3 inflammasome activation, pivotal IL-18 and IL-1β maturation, exacerbating pulmonary disease severity and hampering treatment responses. Following invasion, cells often activate autophagy. Upon thwarting autophagy to fuel pathogen growth, the immune defense transitions to apoptosis and necrosis, tightly regulated by ESAT-6. The involvement of ESAT-6 in necrosis weaves a complex narrative, fostering neutrophil-driven NETosis necrosis. This visual portrayal unveils ESAT-6’s intricate symphony, providing a fresh perspective on tuberculosis immune maneuvers and sparking novel avenues for therapeutic exploration.
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