Author | Costa, Diego L. | |
Author | Amaral, Eduardo P. | |
Author | Namasivayam, Sivaranjani | |
Author | Mittereder, Lara R. | |
Author | Fisher, Logan | |
Author | Bonfim, Caio C. | |
Author | Silva, Aline Sardinha | |
Author | Thompson, Robert W. | |
Author | Hieny, Sara E. | |
Author | Andrade, Bruno de Bezerril | |
Author | Sher, Alan | |
Access date | 2020-09-28T12:12:23Z | |
Available date | 2020-09-28T12:12:23Z | |
Document date | 2020 | |
Citation | COSTA, Diego L. et al. Heme oxygenase-1 inhibition promotes IFNγ- and NOS2- mediated control of Mycobacterium tuberculosis infection. Mucosal Immunology, 2020. | pt_BR |
ISSN | 1933-0219 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/43634 | |
Sponsorship | Intramural Research Program of the NIAID, NIH. This work was
financially supported by the Intramural Research Program of the NIAID, NIH. | pt_BR |
Language | eng | pt_BR |
Publisher | Springer Nature | pt_BR |
Rights | open access | pt_BR |
Subject in Portuguese | Mycobacterium tuberculosis | pt_BR |
Subject in Portuguese | Heme oxigenase | pt_BR |
Subject in Portuguese | Infecção | pt_BR |
Title | Heme oxygenase-1 inhibition promotes IFNγ- and NOS2- mediated control of Mycobacterium tuberculosis infection | pt_BR |
Type | Article | pt_BR |
Abstract | Mycobacterium tuberculosis (Mtb) infection induces pulmonary expression of the heme-degrading enzyme heme oxygenase-1
(HO-1). We have previously shown that pharmacological inhibition of HO-1 activity in experimental tuberculosis results in decreased
bacterial loads and unexpectedly that this outcome depends on the presence of T lymphocytes. Here, we extend these findings by
demonstrating that IFNγ production by T lymphocytes and NOS2 expression underlie this T-cell requirement and that HO-1
inhibition potentiates IFNγ-induced NOS2-dependent control of Mtb by macrophages in vitro. Among the products of heme
degradation by HO-1 (biliverdin, carbon monoxide, and iron), only iron supplementation reverted the HO-1 inhibition-induced
enhancement of bacterial control and this reversal was associated with decreased NOS2 expression and NO production. In addition,
we found that HO-1 inhibition results in decreased labile iron levels in Mtb-infected macrophages in vitro and diminished iron
accumulation in Mtb-infected lungs in vivo. Together these results suggest that the T-lymphocyte dependence of the therapeutic
outcome of HO-1 inhibition on Mtb infection reflects the role of the enzyme in generating iron that suppresses T-cell-mediated
IFNγ/NOS2-dependent bacterial control. In broader terms, our findings highlight the importance of the crosstalk between iron
metabolism and adaptive immunity in determining the outcome of infection. | pt_BR |
Affilliation | National Institutes of Health. National Institutes of Allergy and Infectious Diseases. Bethesda, Maryland, USA. | pt_BR |
Affilliation | National Institutes of Health. National Institutes of Allergy and Infectious Diseases. Bethesda, Maryland, USA. | pt_BR |
Affilliation | National Institutes of Health. National Institutes of Allergy and Infectious Diseases. Bethesda, Maryland, USA. | pt_BR |
Affilliation | National Institutes of Health. National Institutes of Allergy and Infectious Diseases. Bethesda, Maryland, USA. | pt_BR |
Affilliation | National Institutes of Health. National Institutes of Allergy and Infectious Diseases. Bethesda, Maryland, USA. | pt_BR |
Affilliation | National Institutes of Health. National Institutes of Allergy and Infectious Diseases. Bethesda, Maryland, USA. | pt_BR |
Affilliation | National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Parasitic Diseases. Molecular Parasitology Section. Bethesda, MD, USA. | pt_BR |
Affilliation | National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Parasitic Diseases, Helminth Immunology Section. Bethesda, MD, USA. | pt_BR |
Affilliation | National Institutes of Health. National Institutes of Allergy and Infectious Diseases. Bethesda, Maryland, USA. | pt_BR |
Affilliation | National Institutes of Health. National Institutes of Allergy and Infectious Diseases. Bethesda, Maryland, USA / University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Disease Research in Africa. Institute of Infectious Disease and Molecular Medicine. Observatory, Cape Town, South Africa / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brazil / Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil / Universidade Salvador. Laureate Universities. Salvador, BA, Brasil / Escola Bahiana de Medicina e Saúde Pública. Salvador, BA, Brasil / Vanderbilt University. School of Medicine. Department of Medicine. Division of Infectious Diseases. Nashville, TN, USA. | pt_BR |
Affilliation | National Institutes of Health. National Institutes of Allergy and Infectious Diseases. Bethesda, Maryland, USA. | pt_BR |
Subject | Mycobacterium tuberculosis | pt_BR |
Subject | Heme oxigenase | pt_BR |
Subject | Infection | pt_BR |