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Mycobacterium tuberculosis induction of heme Oxygenase-1 expression is Dependent on Oxidative stress and reflects Treatment Outcomes

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Title: Mycobacterium tuberculosis induction of heme Oxygenase-1 expression is Dependent on Oxidative stress and reflects Treatment Outcomes
Authors: Rockwood, N
Costa, DL
Amaral, EP
Du Bruyn, E
Kubler, A
Gil-Santana, L
Fukutani, KF
Scanga, CA
Flynn, JL
Jackson, SH
Wilkinson, KA
Bishai, WR
Sher, A
Wilkinson, RJ
Andrade, BB
Item Type: Journal Article
Abstract: The antioxidant enzyme heme oxygenase-1 (HO-1) is implicated in the pathogenesis of tuberculosis (TB) and has been proposed as a biomarker of active disease. Nevertheless, the mechanisms by which Mycobacterium tuberculosis (Mtb) induces HO-1 as well as how its expression is affected by HIV-1 coinfection and successful antitubercular therapy (ATT) are poorly understood. We found that HO-1 expression is markedly increased in rabbits, mice, and non-human primates during experimental Mtb infection and gradually decreased during ATT. In addition, we examined circulating concentrations of HO-1 in a cohort of 130 HIV-1 coinfected and uninfected pulmonary TB patients undergoing ATT to investigate changes in expression of this biomarker in relation to HIV-1 status, radiological disease severity, and treatment outcome. We found that plasma levels of HO-1 were elevated in untreated HIV-1 coinfected TB patients and correlated positively with HIV-1 viral load and negatively with CD4+ T cell count. In both HIV-1 coinfected and Mtb monoinfected patients, HO-1 levels were substantially reduced during successful TB treatment but not in those who experienced treatment failure or subsequently relapsed. To further delineate the molecular mechanisms involved in induction of HO-1 by Mtb, we performed a series of in vitro experiments using mouse and human macrophages. We found that Mtb-induced HO-1 expression requires NADPH oxidase-dependent reactive oxygen species production induced by the early-secreted antigen ESAT-6, which in turn triggers nuclear translocation of the transcription factor NRF-2. These observations provide further insight into the utility of HO-1 as a biomarker of both disease and successful therapy in TB monoinfected and HIV-TB coinfected patients and reveal a previously undocumented pathway linking expression of the enzyme with oxidative stress.
Issue Date: 12-May-2017
Date of Acceptance: 24-Apr-2017
URI: http://hdl.handle.net/10044/1/49045
DOI: https://dx.doi.org/10.3389/fimmu.2017.00542
ISSN: 1664-3224
Publisher: FRONTIERS MEDIA
Journal / Book Title: FRONTIERS IN IMMUNOLOGY
Volume: 8
Copyright Statement: © 2017 Rockwood, Costa, Amaral, Du Bruyn, Kubler, Gil-Santana, Fukutani, Scanga, Flynn, Jackson, Wilkinson, Bishai, Sher, Wilkinson and Andrade. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY https://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: Science & Technology
Life Sciences & Biomedicine
Immunology
tuberculosis
HIV
heme oxygenase-1
biomarker
oxidative stress
CHRONIC GRANULOMATOUS-DISEASE
ACUTE LUNG INJURY
CARBON-MONOXIDE
HUMAN MACROPHAGES
INNATE IMMUNITY
PULMONARY TUBERCULOSIS
KEAP1-NRF2 SYSTEM
HEMORRHAGIC-SHOCK
GENE-EXPRESSION
REACTIVE OXYGEN
Publication Status: Published
Open Access location: http://journal.frontiersin.org/article/10.3389/fimmu.2017.00542/full
Article Number: ARTN 542
Appears in Collections:Department of Medicine



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