Remodeling the matrix: doxycycline modulates tuberculosis immunopathology

Abstract

Pulmonary cavitation is a hallmark of Mycobacterium tuberculosis (Mtb) infection that provides an immune-privileged niche for extracellular bacillary replication, which associates with increased transmission rates, drug resistance, and chronic lung dysfunction following antituberculous therapy (ATT). Inhibitors of matrix metalloproteinases (MMPs), which are induced by Mtb infection, have shown efficacy in preclinical models and improved microbiologic and immunopathologic outcomes. In this issue of the JCI, Hao Miow et al. performed a double-blind, randomized controlled trial exploring host-directed effects of the MMP inhibitor doxycycline versus placebo when added to standard ATT for pulmonary tuberculosis. Doxycycline treatment over two weeks durably modulated host blood transcription profiles, including the resolution of inflammatory gene programs. Reduced immunopathology markers in doxycycline-treated participants also included improved lung cavity volumes and lower MMP levels in blood and sputum. These findings provide mechanistic insight and momentum for using experimental medicine trials to develop host-directed therapies for tuberculosis.

Figure 1. The effect of doxycycline on pulmonary TB when added to standard therapy.

(i) Aerosolized Mtb is initially contained within lung granulomas where it can remain quiescent or cause progressive pulmonary disease with unrestricted bacterial replication. (ii) In some cases, tissue destruction leads to pulmonary cavitation, which is associated with high mycobacterial burden and poor drug penetration, increasing the risk for transmission and emergent drug resistance. Mtb infection induces MMPs, which regulate inflammatory processes that range from tissue remodeling to tissue destruction (25) and are linked to granuloma maintenance and Mtb dissemination (–12). MMPs also degrade elastin and collagen, contributing to cavitation (13). (iii) Hao Miow et al. explored the effects of doxycycline when added to standard antituberculous therapy in a randomized, placebo-controlled trial of patients with newly diagnosed pulmonary TB (23). Relative to healthy controls, multiple inflammatory gene programs were enriched among pulmonary TB subjects including coexpression modules related to extracellular matrix (ECM) genes. Longitudinal analysis of blood transcriptomes indicated doxycycline reduced transcription of MMP9 and genes related to interferon (IFN) signaling and the innate immune response. These findings mirrored lower levels of MMP proteins in serum (iv) and and lower MMP-1, -8, -9, -12, -13 levels in sputum (ii). This correlated with decreased elastase (potentially including MMP-9 and -12) and collagenase (potentially including MMP-1, -8, -13) enzyme activities in sputum. While the study was underpowered to detect more relevant clinical or microbiologic outcomes, the broad MMP effects of doxycycline correlated with reduced lung cavity volumes (v) at two months, which is notable considering doxycycline was dosed only during the initial two weeks.