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.

Automated summary

The study demonstrated the pathological inhibition effect of doxycycline on matrix metalloproteinases (MMPs) in patients with pulmonary tuberculosis, and it could accelerate the restoration of gene expression. Doxycycline not only reduced the levels of MMPs in sputum of tuberculosis patients, but also inhibited the destruction of collagen and elastin, showing significant differences compared to placebo.