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Mycobacterium tuberculosis Induction of Heme Oxygenase-1 Expression Is Dependent on Oxidative Stress and Reflects Treatment Outcomes.

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.

SUBMITTER: Rockwood N

PROVIDER: S-EPMC5427075 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Mycobacterium tuberculosis Induction of Heme Oxygenase-1 Expression Is Dependent on Oxidative Stress and Reflects Treatment Outcomes.

Rockwood Neesha N Costa Diego L DL Amaral Eduardo P EP Du Bruyn Elsa E Kubler Andre A Gil-Santana Leonardo L Fukutani Kiyoshi F KF Scanga Charles A CA Flynn JoAnne L JL Jackson Sharon H SH Wilkinson Katalin A KA Bishai William R WR Sher Alan A Wilkinson Robert J RJ Andrade Bruno B BB

Frontiers in immunology 20170512

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 < ...[more]

PMID: 28553288

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Project description:Heme oxygenase-1 (HO-1) is a stress response antioxidant enzyme which catalyzes the degradation of heme released during inflammation. HO-1 expression is upregulated in both experimental and human Mycobacterium tuberculosis infection, and in patients it is a biomarker of active disease. Whether the enzyme plays a protective versus pathogenic role in tuberculosis has been the subject of debate. To address this controversy, we administered tin protoporphyrin IX (SnPPIX), a well-characterized HO-1 enzymatic inhibitor, to mice during acute M. tuberculosis infection. These SnPPIX-treated animals displayed a substantial reduction in pulmonary bacterial loads comparable to that achieved following conventional antibiotic therapy. Moreover, when administered adjunctively with antimycobacterial drugs, the HO-1 inhibitor markedly enhanced and accelerated pathogen clearance. Interestingly, both the pulmonary induction of HO-1 expression and the efficacy of SnPPIX treatment in reducing bacterial burden were dependent on the presence of host T lymphocytes. Although M. tuberculosis expresses its own heme-degrading enzyme, SnPPIX failed to inhibit its enzymatic activity or significantly restrict bacterial growth in liquid culture. Together, the above findings reveal mammalian HO-1 as a potential target for host-directed monotherapy and adjunctive therapy of tuberculosis and identify the immune response as a critical regulator of this function. IMPORTANCE:There is no reliable vaccine against tuberculosis (TB), and conventional antibiotic therapy is administered over at least 6 months. This prolonged treatment period can lead to noncompliance resulting in relapsed infection as well as the emergence of multidrug resistance. Thus, there is an urgent need for improved therapeutic regimens that can more rapidly and efficiently control M. tuberculosis in infected patients. Here, we describe a potential strategy for treating TB based on pharmacological inhibition of the host heme-degrading enzyme HO-1. This approach results in significantly reduced bacterial burdens in mice, and when administered in conjunction with conventional antibiotic therapy, leads to faster, more effective pathogen clearance without detectable direct effects on the mycobacteria themselves. Interestingly, the effects of HO-1 inhibition on M. tuberculosis infection in vivo are dependent on the presence of an intact host immune system. These observations establish mammalian HO-1 as a potential target for host-directed therapy of TB.

Project description:Objectives This study was focused on the role of indole acetic acid (IAA) in the defense against oxidative stress damage caused by drought in soybean plants and to elucidate whether heme oxygenase-1 (HO-1) and nitric oxide (NO) are involved in this mechanism. IAA is an auxin that participates in many plant processes including oxidative stress defense, but to the best of our knowledge no information is yet available about its possible action in drought stress. Methods To this end, soybean plants were treated with 8% polyethylene glycol (PEG) or 100 µM IAA. To evaluate the behavior of IAA, plants were pretreated with this compound previous to PEG addition. Lipid peroxidation levels (thiobarbituric acid reactive substances (TBARS)), glutathione (GSH) and ascorbate (AS) contents, catalase (CAT), superoxide dismutase (SOD), and guaiacol peroxidase (POD) activities were determined to evaluate oxidative damage. Results Drought treatment (8% PEG) caused a significant increase in TBARS levels as well as a marked decrease in the non-enzymatic (GSH and AS) and enzymatic (CAT, SOD, and POD) antioxidant defense systems. Pre-treatment with IAA prevented the alterations of stress parameters caused by drought, while treatment with IAA alone did not produce changes in TBARS levels, or GSH and AS contents. Moreover, the activities of the classical enzymes involved in the enzymatic defense system (SOD, CAT, and POD) remained similar to control values. Furthermore, this hormone could enhance HO-1 activity (75% with respect to controls), and this increase was positively correlated with protein content as well as gene expression. The direct participation of HO-1 as an antioxidant enzyme was established by performing experiments in the presence of Zn-protoporphyrin IX, a well-known irreversible inhibitor of this enzyme. It was also demonstrated that HO-1 is modulated by NO, as shown by experiments performed in the presence of an NO donor (sodium nitroprusside), an NO scavenger (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide), or an NO synthesis inhibitor (N-nitro-l-arginine methyl ester, NAME). Discussion It is concluded that IAA is responsible, at least in part, for the protection against oxidative stress caused by drought in soybean plants through the modulation of NO levels which, in turn, enhances HO-1 synthesis and activity.

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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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<i>Mycobacterium tuberculosis</i> Induction of Heme Oxygenase-1 Expression Is Dependent on Oxidative Stress and Reflects Treatment Outcomes.

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