Miow, QH;
Vallejo, AF;
Wang, Y;
Hong, JM;
Bai, C;
Teo, FS;
Wang, AD;
Loh, HR;
Tan, TZ;
Ding, Y;
et al.
Miow, QH; Vallejo, AF; Wang, Y; Hong, JM; Bai, C; Teo, FS; Wang, AD; Loh, HR; Tan, TZ; Ding, Y; She, HW; Gan, SH; Paton, NI; Lum, J; Tay, A; Chee, CB; Tambyah, PA; Polak, ME; Wang, YT; Singhal, A; Elkington, P; Friedland, JS; Ong, CW
(2021)
Doxycycline host-directed therapy in human pulmonary tuberculosis.
J Clin Invest, 131 (15).
e141895.
ISSN 1558-8238
https://doi.org/10.1172/JCI141895
SGUL Authors: Friedland, Jonathan Samuel
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Abstract
BACKGROUND: Matrix metalloproteinases (MMPs) are implicated as key regulators of tissue destruction in tuberculosis (TB) and may be a target for host-directed therapy. Here, we conducted a Phase 2 randomized, double-blind, placebo-controlled trial investigating doxycycline, a licensed broad spectrum MMP inhibitor, in pulmonary TB patients. METHODS: Thirty pulmonary TB patients were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either doxycycline 100 mg or placebo twice a day for 14 days in addition to standard care. RESULTS: There were significant changes in the host transcriptome, and suppression of systemic and respiratory markers of tissue destruction with the doxycycline intervention. Whole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression patterns in TB towards normality, with more rapid down-regulation of type I and II interferon and innate immune response genes and concurrent up-regulation of B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline was discontinued, concurrent with suppression of plasma MMP-1. In respiratory samples, doxycycline reduced MMP-1, -8, -9, -12 and -13 concentrations, suppressed type I collagen and elastin destruction, and reduced pulmonary cavity volume despite unchanged sputum Mycobacterium tuberculosis loads between the study arms. Two weeks of adjunctive doxycycline with standard anti-TB treatment was well-tolerated, with no serious adverse events related to doxycycline. CONCLUSION: These data demonstrate that adjunctive doxycycline with standard anti-TB treatment suppresses pathological MMPs in pulmonary tuberculosis patients, and suggest that larger studies on adjunctive doxycycline to limit immunopathology in TB are merited.
Item Type: | Article | ||||||||||||||||||||||||||||||||||||||||||||||||
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Additional Information: | © 2021 American Society for Clinical Investigation | ||||||||||||||||||||||||||||||||||||||||||||||||
Keywords: | Clinical Trials, Infectious disease, Tuberculosis, Immunology, 11 Medical and Health Sciences | ||||||||||||||||||||||||||||||||||||||||||||||||
Journal or Publication Title: | J Clin Invest | ||||||||||||||||||||||||||||||||||||||||||||||||
ISSN: | 1558-8238 | ||||||||||||||||||||||||||||||||||||||||||||||||
Language: | eng | ||||||||||||||||||||||||||||||||||||||||||||||||
Dates: |
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Publisher License: | Publisher's own licence | ||||||||||||||||||||||||||||||||||||||||||||||||
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PubMed ID: | 34128838 | ||||||||||||||||||||||||||||||||||||||||||||||||
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URI: | https://openaccess.sgul.ac.uk/id/eprint/113447 | ||||||||||||||||||||||||||||||||||||||||||||||||
Publisher's version: | https://doi.org/10.1172/JCI141895 |
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