FIGURE 3.

M.tb induces formation of METs independent of NADPH-oxidase and ROS. Human macrophages release METs upon infection with M.tb. (I) This effect is specially boosted in presence of the so called “cording” or clustered phenotype, that is when the mycobacterium accumulates and clumps together occupying a bigger volume compared to when the bacteria appear disseminated (“non-cording M.tb”). Notably, “cording-M.tb” induces formation of METs in form of threads. (II) Similarly to NETs, M.tb-induced METs are of nuclear origin containing double stranded DNA and citrullinated histones in their composition and M.tb can be found binding to DNA fibers. Furthermore, the mechanism of MET-formation following M.tb infection is regulated by antigen ESAT-6 since an M.tb ESAT-6 deletion mutant blocked METs. M.tb-METs are also regulated by enzyme elastase. However, this mechanism is independent of the enzyme complex NADPH-oxidase and ROS. Interestingly, IFN-γ enhances formation of M.tb-caused METs and induces aggregation of M.tb which in turn leads to increased formation of M.tb-METs, both dependent on ESX-1. Additionally, pre-treatment with IFN-γ promotes cell death of infected macrophages in a ESX-1-dependent manner. Thus, IFN-γ amplifies ESX-1 effects. Created with BioRender.com. M.tb, Mycobacterium tuberculosis; NADPH-oxidase, nicotinamide adenine dinucleotide phosphate oxidase; ROS, reactive oxygen species; METs, macrophage extracellular traps; ESAT-6, early secretory antigenic target 6; ESX-1, early secretory antigenic target 6 secretion system 1; IFN-γ, interferon-gamma.