Doxycycline host-directed therapy in human pulmonary tuberculosis
Qing Hao Miow, … , Jon S. Friedland, Catherine W.M. Ong
Qing Hao Miow, … , Jon S. Friedland, Catherine W.M. Ong
Published June 15, 2021
Citation Information: J Clin Invest. 2021;131(15):e141895. https://doi.org/10.1172/JCI141895.
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Clinical Research and Public Health Infectious disease

Doxycycline host-directed therapy in human pulmonary tuberculosis

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.TRIAL REGISTRATION ClinicalTrials.gov NCT02774993.FUNDING Singapore National Medical Research Council (NMRC/CNIG/1120/2014, NMRC/Seedfunding/0010/2014, NMRC/CISSP/2015/009a); the Singapore Infectious Diseases Initiative (SIDI/2013/013); National University Health System (PFFR-28 January 14, NUHSRO/2014/039/BSL3-SeedFunding/Jul/01); the Singapore Immunology Network Immunomonitoring platform (BMRC/IAF/311006, H16/99/b0/011, NRF2017_SISFP09); an ExxonMobil Research Fellowship, NUHS Clinician Scientist Program (NMRC/TA/0042/2015, CSAINV17nov014); the UK Medical Research Council (MR/P023754/1, MR/N006631/1); a NUS Postdoctoral Fellowship (NUHSRO/2017/073/PDF/03); The Royal Society Challenge Grant (CHG\R1\170084); the Sir Henry Dale Fellowship, Wellcome Trust (109377/Z/15/Z); and A*STAR.

Authors

Qing Hao Miow, Andres F. Vallejo, Yu Wang, Jia Mei Hong, Chen Bai, Felicia S.W. Teo, Alvin D.Y. Wang, Hong Rong Loh, Tuan Zea Tan, Ying Ding, Hoi Wah She, Suay Hong Gan, Nicholas I. Paton, Josephine Lum, Alicia Tay, Cynthia B.E. Chee, Paul A. Tambyah, Marta E. Polak, Yee Tang Wang, Amit Singhal, Paul T. Elkington, Jon S. Friedland, Catherine W.M. Ong

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Figure 3

Doxycycline differentially regulates numerous genes in TB pathway relative to placebo.

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Doxycycline differentially regulates numerous genes in TB pathway relati...
Comparison of gene expression changes (day 14 vs. day 0) between placebo and doxycycline (Doxy) arms for genes in the KEGG TB pathway (map05152) (47–49). The pathway was identified by EGSEA (52) to be significantly regulated by doxycycline treatment (adjusted P = 0.0047). Gene expression changes (day 14 vs. day 0) in the placebo and doxycycline arms are shown on the left and right side, respectively, of each gene box. Red represents upregulation and blue represents downregulation of gene expression.