Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Infection <italic toggle="yes">In Vivo</italic> by a Mechanism Dependent on T Lymphocytes

ABSTRACT 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. Whet...

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Autores principales:	Diego L. Costa, Sivaranjani Namasivayam, Eduardo P. Amaral, Kriti Arora, Alex Chao, Lara R. Mittereder, Mamoudou Maiga, Helena I. Boshoff, Clifton E. Barry, Celia W. Goulding, Bruno B. Andrade, Alan Sher
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/64fdecdf902b4fefb96dcde0a01ffc15
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spelling	oai:doaj.org-article:64fdecdf902b4fefb96dcde0a01ffc152021-11-15T15:50:16ZPharmacological Inhibition of Host Heme Oxygenase-1 Suppresses <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Infection <italic toggle="yes">In Vivo</italic> by a Mechanism Dependent on T Lymphocytes10.1128/mBio.01675-162150-7511https://doaj.org/article/64fdecdf902b4fefb96dcde0a01ffc152016-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01675-16https://doaj.org/toc/2150-7511ABSTRACT 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.Diego L. CostaSivaranjani NamasivayamEduardo P. AmaralKriti AroraAlex ChaoLara R. MitterederMamoudou MaigaHelena I. BoshoffClifton E. BarryCelia W. GouldingBruno B. AndradeAlan SherAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 5 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Diego L. Costa Sivaranjani Namasivayam Eduardo P. Amaral Kriti Arora Alex Chao Lara R. Mittereder Mamoudou Maiga Helena I. Boshoff Clifton E. Barry Celia W. Goulding Bruno B. Andrade Alan Sher Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Infection <italic toggle="yes">In Vivo</italic> by a Mechanism Dependent on T Lymphocytes
description	ABSTRACT 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.
format	article
author	Diego L. Costa Sivaranjani Namasivayam Eduardo P. Amaral Kriti Arora Alex Chao Lara R. Mittereder Mamoudou Maiga Helena I. Boshoff Clifton E. Barry Celia W. Goulding Bruno B. Andrade Alan Sher
author_facet	Diego L. Costa Sivaranjani Namasivayam Eduardo P. Amaral Kriti Arora Alex Chao Lara R. Mittereder Mamoudou Maiga Helena I. Boshoff Clifton E. Barry Celia W. Goulding Bruno B. Andrade Alan Sher
author_sort	Diego L. Costa
title	Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Infection <italic toggle="yes">In Vivo</italic> by a Mechanism Dependent on T Lymphocytes
title_short	Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Infection <italic toggle="yes">In Vivo</italic> by a Mechanism Dependent on T Lymphocytes
title_full	Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Infection <italic toggle="yes">In Vivo</italic> by a Mechanism Dependent on T Lymphocytes
title_fullStr	Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Infection <italic toggle="yes">In Vivo</italic> by a Mechanism Dependent on T Lymphocytes
title_full_unstemmed	Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Infection <italic toggle="yes">In Vivo</italic> by a Mechanism Dependent on T Lymphocytes
title_sort	pharmacological inhibition of host heme oxygenase-1 suppresses <named-content content-type="genus-species">mycobacterium tuberculosis</named-content> infection <italic toggle="yes">in vivo</italic> by a mechanism dependent on t lymphocytes
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/64fdecdf902b4fefb96dcde0a01ffc15
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Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Infection <italic toggle="yes">In Vivo</italic> by a Mechanism Dependent on T Lymphocytes

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