PUBLICATION
Aryl Hydrocarbon Receptor Modulation by Tuberculosis Drugs Impairs Host Defense and Treatment Outcomes
- Authors
- Puyskens, A., Stinn, A., van der Vaart, M., Kreuchwig, A., Protze, J., Pei, G., Klemm, M., Guhlich-Bornhof, U., Hurwitz, R., Krishnamoorthy, G., Schaaf, M., Krause, G., Meijer, A.H., Kaufmann, S.H.E., Moura-Alves, P.
- ID
- ZDB-PUB-200108-2
- Date
- 2019
- Source
- Cell Host & Microbe 27(2): 238-248.e7 (Journal)
- Registered Authors
- Meijer, Annemarie H., Schaaf, Marcel J. M., van der Vaart, Michiel
- Keywords
- AhR, M. marinum, TB, TB drugs, drug metabolism, host-directed therapy, phagocytosis, zebrafish
- MeSH Terms
-
- Animals
- Antitubercular Agents/metabolism*
- Antitubercular Agents/therapeutic use
- Basic Helix-Loop-Helix Transcription Factors/drug effects
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Humans
- Immunity, Cellular/drug effects
- Mycobacterium marinum/drug effects
- Mycobacterium marinum/pathogenicity
- Mycobacterium tuberculosis*/drug effects
- Mycobacterium tuberculosis*/pathogenicity
- Phagocytosis/drug effects
- Receptors, Aryl Hydrocarbon/drug effects*
- Receptors, Aryl Hydrocarbon/metabolism
- Rifabutin/metabolism
- Rifabutin/therapeutic use
- Rifampin/metabolism
- Rifampin/therapeutic use
- THP-1 Cells
- Treatment Outcome
- Tuberculosis/drug therapy*
- Tuberculosis/microbiology
- Zebrafish
- PubMed
- 31901518 Full text @ Cell Host Microbe
Citation
Puyskens, A., Stinn, A., van der Vaart, M., Kreuchwig, A., Protze, J., Pei, G., Klemm, M., Guhlich-Bornhof, U., Hurwitz, R., Krishnamoorthy, G., Schaaf, M., Krause, G., Meijer, A.H., Kaufmann, S.H.E., Moura-Alves, P. (2019) Aryl Hydrocarbon Receptor Modulation by Tuberculosis Drugs Impairs Host Defense and Treatment Outcomes. Cell Host & Microbe. 27(2):238-248.e7.
Abstract
Antimicrobial resistance in tuberculosis (TB) is a public health threat of global dimension, worsened by increasing drug resistance. Host-directed therapy (HDT) is an emerging concept currently explored as an adjunct therapeutic strategy for TB. One potential host target is the ligand-activated transcription factor aryl hydrocarbon receptor (AhR), which binds TB virulence factors and controls antibacterial responses. Here, we demonstrate that in the context of therapy, the AhR binds several TB drugs, including front line drugs rifampicin (RIF) and rifabutin (RFB), resulting in altered host defense and drug metabolism. AhR sensing of TB drugs modulates host defense mechanisms, notably impairs phagocytosis, and increases TB drug metabolism. Targeting AhR in vivo with a small-molecule inhibitor increases RFB-treatment efficacy. Thus, the AhR markedly impacts TB outcome by affecting both host defense and drug metabolism. As a corollary, we propose the AhR as a potential target for HDT in TB in adjunct to canonical chemotherapy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping