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Título : Mycobacterium tuberculosis induction of heme Oxygenase-1 expression is Dependent on Oxidative stress and reflects Treatment Outcomes
Otros títulos : Frontiers in Immunology
Autor : Andrade, Bruno Bezerril
Rockwood, Neesha
Costa, Diego L.
Amaral, Eduardo P.
Bruyn, Elsa Du
Kubler, Andre
Santana, Leonardo Gil
Fukutani, Kiyoshi F.
Scanga, Charles A.
Flynn, JoAnne L.
Jackson, Sharon H.
Wilkinson, Katalin A.
Bishai, William R.
Sher, Alan
Wilkinson, Robert J.
Palabras clave : tuberculosis, HIV, heme oxygenase-1, biomarker, oxidative stress.
Fecha de publicación : 12-may-2017
Resumen : 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.
URI : http://www7.bahiana.edu.br//jspui/handle/bahiana/2944
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