@article{Rockwood2017a,
abstract = {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 induces HO-1 as well as how its expression is affected by HIV-1 co-infection and successful anti-tubercular therapy (ATT) are poorly understood. We found that HO-1 expression is markedly increased in rabbits, mice and non-human primates during experimental M. tuberculosis infection and gradually decreased during ATT. In addition, we examined circulating concentrations of HO-1 in a cohort of 130 HIV-1 co-infected 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 co-infected TB patients and correlated positively with HIV-1 viral load and negatively with CD4+ T cell count. In both HIV-1 co-infected and M. tuberculosis 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 M. tuberculosis, we performed a series of in vitro experiments using mouse and human macrophages. We found that M. tuberculosis induced HO-1 expression requires NADPH-oxidase dependent reactive oxygen species (ROS) 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.},
author = {Rockwood, Neesha and Costa, Diego L and Amaral, Eduardo P and {Du Bruyn}, Elsa and Kubler, Andre and Gil-Santana, Leonardo and Fukutani, Kiyoshi F and Scanga, Charles A and Flynn, JoAnne L and Jackson, Sharon H and Wilkinson, Katalin A and Bishai, William R and Sher, Alan and Wilkinson, Robert J and Andrade, Bruno B},
doi = {10.3389/fimmu.2017.00542},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Rockwood et al. - 2017 - Mycobacterium tuberculosis induction of heme oxygenase-1 expression is dependent on oxidative stress and reflec.pdf:pdf},
journal = {Frontiers in Immunology},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {may},
pages = {542},
pmid = {28553288},
publisher = {Frontiers},
title = {{Mycobacterium tuberculosis induction of heme oxygenase-1 expression is dependent on oxidative stress and reflects treatment outcomes}},
url = {http://journal.frontiersin.org/article/10.3389/fimmu.2017.00542/full},
volume = {8},
year = {2017}
}

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We found that HO-1 expression is markedly increased in rabbits, mice and non-human primates during experimental M. tuberculosis infection and gradually decreased during ATT. In addition, we examined circulating concentrations of HO-1 in a cohort of 130 HIV-1 co-infected 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 co-infected TB patients and correlated positively with HIV-1 viral load and negatively with CD4+ T cell count. In both HIV-1 co-infected and M. tuberculosis 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 M. tuberculosis, we performed a series of in vitro experiments using mouse and human macrophages. We found that M. tuberculosis induced HO-1 expression requires NADPH-oxidase dependent reactive oxygen species (ROS) production induced by the early-secreted antigen ESAT-6 which in turn triggers nuclear translocation of the transcription factor NRF-2. 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