Aryl Hydrocarbon Receptor Modulation by Tuberculosis Drugs Impairs Host Defense and Treatment Outcomes.
Animals
Antitubercular Agents
/ metabolism
Basic Helix-Loop-Helix Transcription Factors
/ drug effects
Humans
Immunity, Cellular
/ drug effects
Mycobacterium marinum
/ drug effects
Mycobacterium tuberculosis
/ drug effects
Phagocytosis
/ drug effects
Receptors, Aryl Hydrocarbon
/ drug effects
Rifabutin
/ metabolism
Rifampin
/ metabolism
THP-1 Cells
Treatment Outcome
Tuberculosis
/ drug therapy
Zebrafish
AhR
M. marinum
TB
TB drugs
drug metabolism
host-directed therapy
phagocytosis
zebrafish
Journal
Cell host & microbe
ISSN: 1934-6069
Titre abrégé: Cell Host Microbe
Pays: United States
ID NLM: 101302316
Informations de publication
Date de publication:
12 02 2020
12 02 2020
Historique:
received:
08
04
2019
revised:
30
10
2019
accepted:
06
12
2019
pubmed:
7
1
2020
medline:
30
9
2020
entrez:
6
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31901518
pii: S1931-3128(19)30634-1
doi: 10.1016/j.chom.2019.12.005
pii:
doi:
Substances chimiques
AHR protein, human
0
Antitubercular Agents
0
Basic Helix-Loop-Helix Transcription Factors
0
Receptors, Aryl Hydrocarbon
0
Rifabutin
1W306TDA6S
Rifampin
VJT6J7R4TR
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
238-248.e7Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.