Isoniazid-induced control of Mycobacterium tuberculosis by primary human cells requires interleukin-1 receptor and tumor necrosis factor.
Proinflammatory cytokines are critical mediators that control Mycobacterium tuberculosis (Mtb) growth during active tuberculosis (ATB). To further inhibit bacterial proliferation in diseased individuals, drug inhibitors of cell wall synthesis such as isoniazid (INH) are employed. However, whether INH presents an indirect effect on bacterial growth by regulating host cytokines during ATB is not well known. To examine this hypothesis, we used an in vitro human granuloma system generated with primary leukocytes from healthy donors adapted to model ATB. Intense Mtb proliferation in cell cultures was associated with monocyte/macrophage activation and secretion of IL-1β and TNF. Treatment with INH significantly reduced Mtb survival, but altered neither T-cell-mediated Mtb killing, nor production of IL-1β and TNF. However, blockade of both IL-1R1 and TNF signaling rescued INH-induced killing, suggesting synergistic roles of these cytokines in mediating control of Mtb proliferation. Additionally, mycobacterial killing by INH was highly dependent upon drug activation by the pathogen catalase-peroxidase KatG and involved a host PI3K-dependent pathway. Finally, experiments using coinfected (KatG-mutated and H37Rv strains) cells suggested that active INH does not directly enhance host-mediated killing of Mtb. Our results thus indicate that Mtb-stimulated host IL-1 and TNF have potential roles in TB chemotherapy.
['Yamashiro|Lívia H|LH|', 'Eto|Carolina|C|', 'Soncini|Marina|M|', 'Horewicz|Verônica|V|', 'Garcia|Magno|M|', 'Schlindwein|Aline D|AD|', 'Grisard|Edmundo C|EC|', 'Rovaris|Darcita B|DB|', 'Báfica|André|A|']
D000995:Antitubercular Agents D001426:Bacterial Proteins D002478:Cells, Cultured D006801:Humans D053583:Interleukin-1beta D007538:Isoniazid D008264:Macrophages D009000:Monocytes D009169:Mycobacterium tuberculosis D019869:Phosphatidylinositol 3-Kinases D017472:Receptors, Interleukin-1 D014376:Tuberculosis D014409:Tumor Necrosis Factor-alpha
Mycobacterium tuberculosis Human Isoniazid Leukocytes TNF IL-1