Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses Mycobacterium tuberculosis Infection In Vivo by a Mechanism Dependent on T Lymphocytes

NIAID, NIH. Laboratory of Parasitic Diseases. Immunobiology Section. Bethesda, MD, USA
NIAID, NIH. Laboratory of Parasitic Diseases. Immunobiology Section. Bethesda, MD, USA
NIAID, NIH. Laboratory of Parasitic Diseases. Immunobiology Section. Bethesda, MD, USA
NIAID, NIH. Laboratory of Clinical Infectious Diseases. Tuberculosis Research Section. Bethesda, MD, USA
University of California. Department of Pharmaceutical Sciences. Irvine, CA, USA
NIAID, NIH. Laboratory of Parasitic Diseases. Immunobiology Section. Bethesda, MD, USA
NIAID, NIH. Laboratory of Parasitic Diseases. Immunobiology Section. Bethesda, MD, USA
NIAID, NIH. Laboratory of Clinical Infectious Diseases. Tuberculosis Research Section. Bethesda, MD, USA
NIAID, NIH. Laboratory of Clinical Infectious Diseases. Tuberculosis Research Section. Bethesda, MD, USA
University of California. Department of Molecular Biology and Biochemistry. Irvine, CA, USA / University of California. Departmente of Pharmaceutical Sciences. Irvine, CA, USA
NIAID, NIH. Laboratory of Parasitic Diseases. Immunobiology Section. Bethesda, MD, USA / Fundação Oswaldo Cruz. Instituto de Pesquisas Gonçalo Moniz. Unidade de Medicina Investigativa. Laboratório Integrado de Microbiologia e Imunorregulação. Salvador, BA, Brasil / Fundação José Silveira. Instituto Brasileiro para a Investigação da Tuberculose. Multinational Organization Network Sponsoring Translational and Epidemiological Research. Salvador, BA, Brasil
NIAID, NIH. Laboratory of Parasitic Diseases. Immunobiology Section. Bethesda, MD, USA

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.

Keywords in Portuguese

Mycobacterium tuberculosis
Heme oxigenase
Infecção
Humanos
Antibióticos
Tuberculose

Keywords

Mycobacterium tuberculosis
Heme oxygenase
Infection
Humans
Antibiotic
Tuberculosis

Publisher

American Society for Microbiology

Citation

COSTA, D. L. et al. Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses Mycobacterium tuberculosis Infection In Vivo by a Mechanism Dependent on T Lymphocytes. mBio, v. 7, n. 5, p. e01675-16, 2016.

DOI

10.1128/mBio.01675-16

ISSN

2150-7511

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/18119

Type

Copyright

Open access

Collections

Share

Statistics

Metadata

Author

Affilliation