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 2

Doxycycline results in faster normalization of type II interferon and innate immune response genes relative to placebo.

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Doxycycline results in faster normalization of type II interferon and in...
(A and B) PCA analysis of doxycycline-treated (A) and placebo-treated (B) patients at day 0 (orange) and day 14 (blue). First 2 components of PCA are shown and their variances are shown in parenthesis. Doxycycline reduces variation between individuals over the first 2 weeks of treatment. Only patients with day 0 and day 14 samples are plotted. n = 8 placebo, n = 7 doxycycline. (C) Transcript to transcript clustering of 12,977 genes filtered and normalized using TMM identified 27 coexpressed clusters (Pearson r = 0.8; MCL = 1.7; n gene/cluster: 3/10) over the course of doxycycline treatment. The 15 largest clusters (Supplemental Table 3) are shown in different colors. Lines represent the similarity between transcripts, circles represent individual genes. Two major groupings identify genes preferentially expressed in innate immune response (granulocytes, interferon response) and adaptive immune response (T cells). (D–I) Longitudinal analysis of selected genes, IRF1 (D), APOL1 (E), FCGR1A (F), FCGR1B (G), GBP5 (H), and GBP6 (I) from a cluster encoding for type II interferon and innate immune responses. TMM normalized gene expression at days 0, 14, and 56 of patients with TB in placebo (n = 8, green) and doxycycline (Doxy, n = 7, purple) arms, and baseline expression of healthy volunteers (HV, n = 6, blue) are plotted. Box represents 25th and 75th percentile, line is median, with whiskers denoting extremes.