Mycobacterium tuberculosis Exploits Human Interferon γ to Stimulate Macrophage Extracellular Trap Formation and Necrosis

Human neutrophils form extracellular traps during M. tuberculosis infection, but a similar phenomenon has not been reported in human macrophages. Here we demonstrate that M. tuberculosis induces release of extracellular traps from human macrophages. This process is regulated by elastase activity, previously shown to regulate formation of extracellular traps by neutrophils. Interestingly, formation of extracellular traps by macrophages during M. tuberculosis infection is inducible by interferon gamma (IFN-gamma). These traps are mainly produced by heavily infected macrophages. Accordingly, IFN-gamma is found to stimulate M. tuberculosis aggregation in macrophages. Both IFN-gamma-inducible events, extracellular trap formation and mycobacterial aggregation, require the ESX-1 secretion system. In addition, IFN-gamma is found to enhance ESX-1-mediated macrophage necrosis. In the absence of ESX-1, IFN-gamma does not restore any extracellular trap formation, mycobacterial aggregation, or macrophage necrosis. Thus, initial characterization of macrophage extracellular trap formation due to M. tuberculosis infection led to the uncovering of a novel role for IFN-gamma in amplifying multiple effects of the mycobacterial ESX-1.