Aryl Hydrocarbon Receptor Modulation by Tuberculosis Drugs Impairs Host Defense and Treatment Outcomes.

Aryl Hydrocarbon Receptor Modulation by Tuberculosis Drugs Impairs Host Defense and Treatment Outcomes.
Cell Host Microbe. 2019 Dec 23;:
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 AH, Kaufmann SHE, Moura-Alves P
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.
PMID: 31901518 [PubMed - as supplied by publisher]

Source: Cell Host and Microbe - December 22, 2019 Category: Microbiology 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 AH, Kaufmann SHE, Moura-Alves P Tags: Cell Host Microbe Source Type: research