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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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 4

Doxycycline leads to greater downregulation of type I interferon responses and extracellular matrix genes, and upregulation of B cells markers relative to placebo.

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Doxycycline leads to greater downregulation of type I interferon respons...
(A) GSEA of DEGs specific to doxycycline treatment ((Doxy_Day14-Doxy_Day0)–(Placebo_Day14-Placebo_Day0)). Blood transcriptional modules (54) were used as gene sets. The top 15 enriched gene sets are shown. Dotted line marks adjusted P = 0.05. Red represents upregulation and blue represents downregulation of gene sets. (B–D) Longitudinal analysis of type I interferon response gene set (M127) (B), extracellular matrix gene set (M2.0) (C), and MMP9 (D) at day 0 and day 14 of placebo (n = 8, green) and doxycycline (n = 7, purple) arms. Median expression levels of genes in the gene sets are plotted, while TMM normalized gene expressions are shown for MMP9. Box represents 25th and 75th percentile, line is median, with whiskers denoting extremes. **Adjusted P < 0.01.