Mycobacteria inhibit neutrophil recruitment to avoid neutrophil-assisted killing by macrophages

Neutrophils migrate rapidly to sites of bacterial infection where they mount critical first-line defenses. Puzzlingly, neutrophils are scant at initial sites of tuberculosis infection. Here, in the zebrafish model of tuberculosis, we find that mycobacteria actively inhibit neutrophil recruitment. Upon being phagocytosed by first-responding tissue resident macrophages, mycobacteria use their ESX-1 virulence locus to induce these cells to produce lipoxins, potent inhibitors of neutrophil migration. Inhibition of neutrophils is integral to the mycobacterial strategy to establish infection. While neutrophils are unable to kill the infecting mycobacteria directly, they induce the infected macrophages to do so. Neutrophil secreted myeloperoxidase interacts with macrophage mannose receptors to induce tumor necrosis factor that increases macrophage microbicidal activity. Our work unmasks a neutrophil-macrophage interaction that, when enabled, potentiates mycobacterial eradication. We find that zileuton, an orally active inhibitor of lipoxin synthesis, promotes neutrophil recruitment and early mycobacterial clearance, suggesting its therapeutic potential to prevent tuberculosis.