Journal Article

Doxycycline host-directed therapy in human pulmonary tuberculosis

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

2021

Overview

BACKGROUNDMatrix 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.METHODSThirty 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.RESULTSWhole 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.CONCLUSIONAdjunctive doxycycline with standard anti-TB treatment suppressed pathological MMPs in PTB patients. Larger studies on adjunctive doxycycline to limit TB immunopathology are merited.TRIAL REGISTRATIONClinicalTrials.gov NCT02774993.FUNDINGSingapore 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.

• Publisher: American Society for Clinical Investigation
• Subject: Adult / Clinical Medicine / Collagenases - biosynthesis / Double-Blind Method / Doxycycline / Doxycycline - administration & dosage / Drug therapy / Female / Gene Expression Regulation, Enzymologic - drug effects / Health aspects / Host-bacteria relationships / Humans / Male / Middle Aged / Molecular targeted therapy / Pulmonary tuberculosis / RNA-Seq / Testing / Tuberculosis, Pulmonary - drug therapy / Tuberculosis, Pulmonary - enzymology