TABLE 1.
M. tb virulence factors affecting NETs/METs.
| M.tb virulence factor | Effect | References |
| ESAT-6 | - ESAT-6 causes necrosis of neutrophils. - ESAT-6 has a leukocidin-like action, promoting increased levels of intracellular Ca2+ in aging neutrophils leading to calpain activation. - ESAT-6-stimulated neutrophils produced NETs colocalizing with MPO in a Ca2+ dependent manner. |
Francis et al., 2014 |
| - Essential for the formation of METs by human macrophages upon cord-forming M.tb infection. | Kalsum et al., 2017 | |
| - ESAT-6 together with neutrophil-derived ROS is a prerequisite for M.tb-infected neutrophils to undergo necrosis. - When inhibiting necrosis of M.tb infected-neutrophils, mycobacterial growth was blocked. - ESAT-6 is essential for mycobacterial growth in macrophages and neutrophils. - ESAT-6-induced neutrophil necrosis drives early direct contact between M.tb and the phagosomal membrane within macrophages. |
Dallenga et al., 2017 | |
| - ESAT-6 induces nuclear changes in neutrophils such as DNA extrusion, chromatin decondensation and nuclear swelling, suggestive of NETosis. ESAT-6 nuclear changes in neutrophils were similar to those produced by sera from patients with ATB. - ESAT-6 resulted in a more potent inducer of nuclear changes in neutrophils than CFP-10, and were also comparable to those induced by PMA. |
Rojas-Espinosa et al., 2021 | |
| - An M.tb ESX-1 deletion mutant did not induce macrophage colony-stimulating factor (M-CSF)–differentiated macrophages to form ETs. - ESX-1 induces necrosis of macrophages and this is potentiated by human IFN-γ. |
Wong and Jacobs, 2013 | |
| CFP-10 | - Involved in the induction of nuclear changes in neutrophils (DNA extrusion, chromatin decondensation and nuclear swelling) similar to those induced by PMA, a positive control for NETosis, although to a lesser extent than ESAT-6. | Rojas-Espinosa et al., 2021 |
| - Induce release of intracellular Ca2+ in human neutrophils in a NADPH-oxidase dependent manner. - CFP-10 significantly induced migration of neutrophils and primed neutrophils triggered ROS production when stimulated with CFP-10. |
Welin et al., 2015 | |
| Rv0888 sphingomyelinase (SpmT) | - MPO, citrullinated H3 and histone H4 were detected in the lung and bronchoalveolar lavage fluid of mice infected with recombinant Rv0888. - NETs-mediated lung injury promoted release of the inflammatory cytokines IL-6, TNF-α and IL-1β. - Rv0888 sphingomyelinase activity induced NETs in the lungs of mice in a ROS-dependent manner and in vitro in human neutrophils, contributing to lung injury. - Depletion of sphingomyelin by sphingomyelinase leads to an increase in the formation of NETs. |
Dang et al., 2018 |
| - Enhances replication of M.tb in human macrophages. | Speer et al., 2015 | |
| - Rv0888 is essential for M.tb to be phagocytosed. | Niekamp et al., 2021 |