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dc.titleDoxycycline host-directed therapy in human pulmonary tuberculosis.
dc.contributor.authorMIOW QING HAO
dc.contributor.authorVallejo, Andres F
dc.contributor.authorWang, Yu
dc.contributor.authorHONG JIA MEI
dc.contributor.authorBAI CHEN
dc.contributor.authorTeo, Felicia Sw
dc.contributor.authorWang, Alvin Dingyuan
dc.contributor.authorLoh, Hong Rong
dc.contributor.authorTan Tuan Zea
dc.contributor.authorDing, Ying
dc.contributor.authorShe, Hoi Wah
dc.contributor.authorGan, Suay Hong
dc.contributor.authorPaton, Nicholas I
dc.contributor.authorLum, Josephine
dc.contributor.authorTay, Alicia
dc.contributor.authorChee, Cynthia Be
dc.contributor.authorPAUL ANANTHARAJAH TAMBYAH
dc.contributor.authorPolak, Marta E
dc.contributor.authorWang, Yee Tang
dc.contributor.authorSinghal, Amit
dc.contributor.authorElkington, Paul
dc.contributor.authorFriedland, Jon S
dc.contributor.authorCATHERINE ONG WEI MIN
dc.identifier.citationMIOW QING HAO, Vallejo, Andres F, Wang, Yu, HONG JIA MEI, BAI CHEN, Teo, Felicia Sw, Wang, Alvin Dingyuan, Loh, Hong Rong, Tan Tuan Zea, Ding, Ying, She, Hoi Wah, Gan, Suay Hong, Paton, Nicholas I, Lum, Josephine, Tay, Alicia, Chee, Cynthia Be, PAUL ANANTHARAJAH TAMBYAH, Polak, Marta E, Wang, Yee Tang, Singhal, Amit, Elkington, Paul, Friedland, Jon S, CATHERINE ONG WEI MIN (2021-06-15). Doxycycline host-directed therapy in human pulmonary tuberculosis.. Journal of Clinical Investigation. ScholarBank@NUS Repository.
dc.description.abstractBACKGROUND: Matrix metalloproteinases (MMPs) are implicated as key regulators of tissue destruction in tuberculosis (TB) and may be a target for host-directed therapy. Here, we conducted a Phase 2 randomized, double-blind, placebo-controlled trial investigating doxycycline, a licensed broad spectrum MMP inhibitor, in pulmonary TB patients. METHODS: Thirty pulmonary TB patients were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either doxycycline 100 mg or placebo twice a day for 14 days in addition to standard care. RESULTS: There were significant changes in the host transcriptome, and suppression of systemic and respiratory markers of tissue destruction with the doxycycline intervention. Whole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression patterns in TB towards normality, with more rapid down-regulation of type I and II interferon and innate immune response genes and concurrent up-regulation of B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline was discontinued, concurrent with suppression of plasma MMP-1. In respiratory samples, doxycycline reduced MMP-1, -8, -9, -12 and -13 concentrations, suppressed type I collagen and elastin destruction, and reduced pulmonary cavity volume despite unchanged sputum Mycobacterium tuberculosis loads between the study arms. Two weeks of adjunctive doxycycline with standard anti-TB treatment was well-tolerated, with no serious adverse events related to doxycycline. CONCLUSION: These data demonstrate that adjunctive doxycycline with standard anti-TB treatment suppresses pathological MMPs in pulmonary tuberculosis patients, and suggest that larger studies on adjunctive doxycycline to limit immunopathology in TB are merited.
dc.publisherAmerican Society for Clinical Investigation
dc.subjectClinical Trials
dc.subjectInfectious disease
dc.contributor.departmentDEPT OF MEDICINE
dc.description.sourcetitleJournal of Clinical Investigation
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