ESAT-6 a Major Virulence Factor of Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), is one of the most successfully adapted human pathogens. Human-to-human transmission occurs at high rates through aerosols containing bacteria, but the pathogen evolved prior to the establishment of crowded populations. Mtb has developed a particular strategy to ensure persistence in the host until an opportunity for transmission arises. It has refined its lifestyle to obviate the need for virulence factors such as capsules, flagella, pili, or toxins to circumvent mucosal barriers. Instead, the pathogen uses host macrophages, where it establishes intracellular niches for its migration into the lung parenchyma and other tissues and for the induction of long-lived latency in granulomas. Finally, at the end of the infection cycle, Mtb induces necrotic cell death in macrophages to escape to the extracellular milieu and instructs a strong inflammatory response that is required for the progression from latency to disease and transmission. Common to all these events is ESAT-6, one of the major virulence factors secreted by the pathogen. This narrative review highlights the recent advances in understanding the role of ESAT-6 in hijacking macrophage function to establish successful infection and transmission and its use as a target for the development of diagnostic tools and vaccines.

Modulation of Cystatin F in Human Macrophages Impacts Cathepsin-Driven Killing of Multidrug-Resistant Mycobacterium tuberculosis

“…Human tuberculosis (TB) caused by the species Mycobacterium tuberculosis (Mtb) represents one of the deadliest infections in the world [ 1 ]. Mtb is a highly successful pathogen that primarily affects the lungs, leading to pulmonary TB, a condition required for transmission [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. The infection of other organs and tissues may also occur during extrapulmonary TB but constitutes a dead end for the pathogen [ 3 , 4 , 9 ].…”

Ethambutol and meropenem/clavulanate synergy promotes enhanced extracellular and intracellular killing of Mycobacterium tuberculosis

“…Recognition of the released PAMPs by intracellular PRRs, including NOD2, NLRP3, and AIM2, triggers NFκB-dependent and inflammasome-mediated pro-inflammatory cytokine production ( 52 – 55 ). In accordance with an earlier study ( 56 ), we did not observe signs that therapeutically relevant MEM concentrations negatively affected cell viability over time, but the addition of the higher concentration of the carbapenem during infection with strain MDR III did induce a higher degree of macrophage necrosis.…”

The role of ESAT-6 in tuberculosis immunopathology

“…The first is protective limitation, because although CD4 T cells are maintained in the lung parenchyma due to continuous antigenic stimulation, protective immunity is limited by functional exhaustion. The second, which would revolutionize the line of modern immunodiagnostics, is that an ESAT-6 vaccine would influencing in the well established tests (interferon gamma release assay (IGRA) and the tuberculin skin test (TST)), thus limiting the ability to distinguish immunized from infected people and the development of IGRA tests without ESAT-6 would be necessary ( 87 ). However, although the adaptive immunity developed by ESAT-6 is essential for the development of vaccines, during the latent phase of the disease it also favors the formation of the adaptive granuloma ( 88 ).…”

“…Within this intricate milieu, a delicate interplay unfolds between pro-inflammatory microbicidal mechanisms and immunosuppressive processes. CD4+ effector T cells, including Th1 producing IFNγ and TNFα, Th17 secreting IL-17, and a smaller contingent of Th2 and regulatory T cells, orchestrate this balance ( 87 , 108 ).…”