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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
immunology and microbiology
Pharmacological inhibition of host heme oxygenase-1 suppresses mycobacterium tuberculosis infection in vivo by a mechanism dependent on T lymphocytes
mBio, Volume 7, No. 5, Article e01675-16, Year 2016
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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 wellcharacterized 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. © 2016 Costa et al.
Authors & Co-Authors
Costa, Diego Luís
United States, Bethesda
National Institutes of Health Nih
Namasivayam, Sivaranjani
United States, Bethesda
National Institutes of Health Nih
Amaral, Eduardo Pinheiro
United States, Bethesda
National Institutes of Health Nih
Arora, Kriti
United States, Bethesda
National Institutes of Health Nih
Mittereder, Lara R.
United States, Bethesda
National Institutes of Health Nih
Maiga, Mamoudou
United States, Bethesda
National Institutes of Health Nih
Boshoff, Helena Ingrid M.
United States, Bethesda
National Institutes of Health Nih
Barry, Clifton Earl
United States, Bethesda
National Institutes of Health Nih
Andrade, Bruno B.
United States, Bethesda
National Institutes of Health Nih
Brazil, Rio de Janeiro
Fundacao Oswaldo Cruz
Brazil, Salvador
Fundação José Silveira
Sher, Alan F.
United States, Bethesda
National Institutes of Health Nih
Statistics
Citations: 39
Authors: 10
Affiliations: 4
Identifiers
Doi:
10.1128/mBio.01675-16
ISSN:
21612129
Research Areas
Infectious Diseases