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Isoniazid-induced control ofMycobacterium tuberculosisby primary human cells requires interleukin-1 receptor and tumor necrosis factor

Authors :
Verônica Vargas Horewicz
Darcita Rovaris
Carolina Eto
Lívia H. Yamashiro
Aline Daiane Schlindwein
Magno D. Garcia
André Báfica
Edmundo C. Grisard
Marina Soncini
Source :
European Journal of Immunology. 46:1936-1947
Publication Year :
2016
Publisher :
Wiley, 2016.

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.

Details

ISSN :
00142980
Volume :
46
Database :
OpenAIRE
Journal :
European Journal of Immunology
Accession number :
edsair.doi.dedup.....6ceeaba3881e3c04909ecb04744e5241
Full Text :
https://doi.org/10.1002/eji.201646349