title: Isoniazid-induced control of Mycobacterium tuberculosis by primary human cells requires interleukin-1 receptor and tumor necrosis factor.
abstract: 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.
authors.affiliation: Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil.
authors.forename: Lívia H
authors.initials: LH
authors.lastname: Yamashiro
authors.affiliation: Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil.
authors.forename: Carolina
authors.initials: C
authors.lastname: Eto
authors.affiliation: Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil.
authors.forename: Marina
authors.initials: M
authors.lastname: Soncini
authors.affiliation: Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil.
authors.forename: Verônica
authors.initials: V
authors.lastname: Horewicz
authors.affiliation: Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil.
authors.forename: Magno
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Laboratory of Protozoology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil.|Central Public Health Laboratory/LACEN, Florianópolis, Brazil.
authors.forename: Aline D
authors.initials: AD
authors.lastname: Schlindwein
authors.affiliation: Laboratory of Protozoology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil.
authors.forename: Edmundo C
authors.initials: EC
authors.lastname: Grisard
authors.affiliation: Central Public Health Laboratory/LACEN, Florianópolis, Brazil.
authors.forename: Darcita B
authors.initials: DB
authors.lastname: Rovaris
authors.affiliation: Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil.
authors.forename: André
authors.initials: A
authors.lastname: Báfica
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology*; D007538:Isoniazid / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000276:immunology*; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases; D007538:Isoniazid
keywords: Human; IL-1; Isoniazid; Leukocytes; Mycobacterium tuberculosis; TNF