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Doxycycline host-directed therapy in human pulmonary tuberculosis

Doxycycline host-directed therapy in human pulmonary tuberculosis
Doxycycline host-directed therapy in human pulmonary tuberculosis

BACKGROUND. Matrix metalloproteinases (MMPs) are key regulators of tissue destruction in tuberculosis (TB) and may be targets for host-directed therapy. We conducted a phase II double-blind, randomized, controlled trial investigating doxycycline, a licensed broad-spectrum MMP inhibitor, in patients with pulmonary TB. METHODS. Thirty patients with pulmonary TB were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either 100 mg doxycycline or placebo twice a day for 14 days, in addition to standard care. RESULTS. Whole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression in TB towards normality, rapidly down-regulating type I and II interferon and innate immune response genes, and up-regulating B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline discontinuation, concurrent with suppressed plasma MMP-1. Doxycycline significantly reduced sputum MMP-1, -8, -9, -12 and -13, suppressed type I collagen and elastin destruction, reduced pulmonary cavity volume without altering sputum mycobacterial loads, and was safe. CONCLUSION. Adjunctive doxycycline with standard anti-TB treatment suppressed pathological MMPs in PTB patients. Larger studies on adjunctive doxycycline to limit TB immunopathology are merited.

0021-9738
Miow, Quig
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Vallejo Pulido, Andres
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Wang, Yu
f930e0ef-43aa-4663-8bf4-41d0f84ab682
Hong, Jia
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Bai, Chen
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Teo, Felicia
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Wang, Alvin
39fc12b9-9ca7-4cf3-8b3f-39bf3e26452e
Loh, Hong
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Tan, Tuan
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Ding, Ying
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She, Hoi
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Gan, Suay
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Paton, Nicholas
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Lum, Josephine
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Tay, Alicia
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Chee, Cynthia
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Tambyah, Paul
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Polak, Marta
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Wang, Yee
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Singhal, Amit
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Elkington, Paul
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Friedland, Jon S.
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Ong, Catherine W.M.
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Miow, Quig
ca3d1b2a-3ea7-4575-98bb-7705e5599306
Vallejo Pulido, Andres
27bc0b94-0c40-4fd1-9533-7e267d588c0a
Wang, Yu
f930e0ef-43aa-4663-8bf4-41d0f84ab682
Hong, Jia
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Bai, Chen
d741eaab-bcc3-4bfd-b64f-ed76739db933
Teo, Felicia
229681e2-180d-4015-aa4a-de2b29d63af8
Wang, Alvin
39fc12b9-9ca7-4cf3-8b3f-39bf3e26452e
Loh, Hong
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Tan, Tuan
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Ding, Ying
a89e2def-361c-43ef-a807-b2a76f939875
She, Hoi
c454f109-8e3e-4eb8-9ea9-f3465bac403a
Gan, Suay
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Paton, Nicholas
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Lum, Josephine
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Tay, Alicia
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Chee, Cynthia
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Tambyah, Paul
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Polak, Marta
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Wang, Yee
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Singhal, Amit
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Elkington, Paul
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Friedland, Jon S.
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Ong, Catherine W.M.
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Miow, Quig, Vallejo Pulido, Andres, Wang, Yu, Hong, Jia, Bai, Chen, Teo, Felicia, Wang, Alvin, Loh, Hong, Tan, Tuan, Ding, Ying, She, Hoi, Gan, Suay, Paton, Nicholas, Lum, Josephine, Tay, Alicia, Chee, Cynthia, Tambyah, Paul, Polak, Marta, Wang, Yee, Singhal, Amit, Elkington, Paul, Friedland, Jon S. and Ong, Catherine W.M. (2021) Doxycycline host-directed therapy in human pulmonary tuberculosis. Journal of Clinical Investigation, 131 (15), [e14i895]. (doi:10.1172/JCI141895).

Record type: Article

Abstract

BACKGROUND. Matrix metalloproteinases (MMPs) are key regulators of tissue destruction in tuberculosis (TB) and may be targets for host-directed therapy. We conducted a phase II double-blind, randomized, controlled trial investigating doxycycline, a licensed broad-spectrum MMP inhibitor, in patients with pulmonary TB. METHODS. Thirty patients with pulmonary TB were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either 100 mg doxycycline or placebo twice a day for 14 days, in addition to standard care. RESULTS. Whole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression in TB towards normality, rapidly down-regulating type I and II interferon and innate immune response genes, and up-regulating B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline discontinuation, concurrent with suppressed plasma MMP-1. Doxycycline significantly reduced sputum MMP-1, -8, -9, -12 and -13, suppressed type I collagen and elastin destruction, reduced pulmonary cavity volume without altering sputum mycobacterial loads, and was safe. CONCLUSION. Adjunctive doxycycline with standard anti-TB treatment suppressed pathological MMPs in PTB patients. Larger studies on adjunctive doxycycline to limit TB immunopathology are merited.

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Accepted_141895-JCI-CMED-RV-3_ms_511511 - Accepted Manuscript
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Accepted/In Press date: 11 June 2021
e-pub ahead of print date: 15 June 2021
Published date: 15 June 2021

Identifiers

Local EPrints ID: 449845
URI: http://eprints.soton.ac.uk/id/eprint/449845
ISSN: 0021-9738
PURE UUID: 91a85a92-bde6-47c3-ba3d-2e4103bf9499
ORCID for Andres Vallejo Pulido: ORCID iD orcid.org/0000-0002-4688-0598
ORCID for Paul Elkington: ORCID iD orcid.org/0000-0003-0390-0613

Catalogue record

Date deposited: 22 Jun 2021 16:30
Last modified: 26 Nov 2021 03:10

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Contributors

Author: Quig Miow
Author: Andres Vallejo Pulido ORCID iD
Author: Yu Wang
Author: Jia Hong
Author: Chen Bai
Author: Felicia Teo
Author: Alvin Wang
Author: Hong Loh
Author: Tuan Tan
Author: Ying Ding
Author: Hoi She
Author: Suay Gan
Author: Nicholas Paton
Author: Josephine Lum
Author: Alicia Tay
Author: Cynthia Chee
Author: Paul Tambyah
Author: Marta Polak
Author: Yee Wang
Author: Amit Singhal
Author: Paul Elkington ORCID iD
Author: Jon S. Friedland
Author: Catherine W.M. Ong

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