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Isoniazid-induced control ofMycobacterium tuberculosisby primary human cells requires interleukin-1 receptor and tumor necrosis factor
- 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.
- Subjects :
- 0301 basic medicine
Interleukin-1beta
Immunology
Antitubercular Agents
Biology
Interleukin-1 receptor
Monocytes
Microbiology
Proinflammatory cytokine
Mycobacterium tuberculosis
Phosphatidylinositol 3-Kinases
03 medical and health sciences
0302 clinical medicine
Bacterial Proteins
Isoniazid
medicine
Humans
Tuberculosis
Immunology and Allergy
Macrophage
Secretion
Cells, Cultured
Tumor Necrosis Factor-alpha
Macrophages
Monocyte
Receptors, Interleukin-1
respiratory system
bacterial infections and mycoses
biology.organism_classification
030104 developmental biology
medicine.anatomical_structure
Tumor necrosis factor alpha
030215 immunology
medicine.drug
Subjects
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