Mycobacterium tuberculosis induction of heme oxygenase-1 expression is dependent on oxidative stress and reflects treatment outcomes

Neesha Rockwood, Diego L. Costa, Eduardo P. Amaral, Elsa Du Bruyn, Andre Kubler, Leonardo Gil-Santana, Kiyoshi F. Fukutani, Charles A. Scanga, Jo Anne L. Flynn, Sharon H. Jackson, Katalin A. Wilkinson, William R. Bishai, Alan Sher, Robert J. Wilkinson, Bruno B. Andrade

Research output: Contribution to journalArticle

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 (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.

Original languageEnglish (US)
Article number542
JournalFrontiers in Immunology
Volume8
Issue numberMAY
DOIs
StatePublished - May 12 2017

Fingerprint

Heme Oxygenase-1
Mycobacterium tuberculosis
Oxidative Stress
HIV-1
Tuberculosis
Biological Markers
Enzymes
Mycobacterium Infections
NADPH Oxidase
Viral Load
Treatment Failure
Coinfection
Pulmonary Tuberculoses
Primates
Reactive Oxygen Species
Transcription Factors
Cell Count
Antioxidants
Macrophages
HIV

Keywords

  • Biomarker
  • Heme oxygenase-1
  • HIV
  • Oxidative stress
  • Tuberculosis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Rockwood, N., Costa, D. L., Amaral, E. P., Du Bruyn, E., Kubler, A., Gil-Santana, L., ... Andrade, B. B. (2017). Mycobacterium tuberculosis induction of heme oxygenase-1 expression is dependent on oxidative stress and reflects treatment outcomes. Frontiers in Immunology, 8(MAY), [542]. DOI: 10.3389/fimmu.2017.00542

Mycobacterium tuberculosis induction of heme oxygenase-1 expression is dependent on oxidative stress and reflects treatment outcomes. / Rockwood, Neesha; Costa, Diego L.; Amaral, Eduardo P.; Du Bruyn, Elsa; Kubler, Andre; Gil-Santana, Leonardo; Fukutani, Kiyoshi F.; Scanga, Charles A.; Flynn, Jo Anne L.; Jackson, Sharon H.; Wilkinson, Katalin A.; Bishai, William R.; Sher, Alan; Wilkinson, Robert J.; Andrade, Bruno B.

In: Frontiers in Immunology, Vol. 8, No. MAY, 542, 12.05.2017.

Research output: Contribution to journalArticle

Rockwood, N, Costa, DL, Amaral, EP, Du Bruyn, E, Kubler, A, Gil-Santana, L, Fukutani, KF, Scanga, CA, Flynn, JAL, Jackson, SH, Wilkinson, KA, Bishai, WR, Sher, A, Wilkinson, RJ & Andrade, BB 2017, 'Mycobacterium tuberculosis induction of heme oxygenase-1 expression is dependent on oxidative stress and reflects treatment outcomes' Frontiers in Immunology, vol 8, no. MAY, 542. DOI: 10.3389/fimmu.2017.00542
Rockwood N, Costa DL, Amaral EP, Du Bruyn E, Kubler A, Gil-Santana L et al. Mycobacterium tuberculosis induction of heme oxygenase-1 expression is dependent on oxidative stress and reflects treatment outcomes. Frontiers in Immunology. 2017 May 12;8(MAY). 542. Available from, DOI: 10.3389/fimmu.2017.00542

Rockwood, Neesha; Costa, Diego L.; Amaral, Eduardo P.; Du Bruyn, Elsa; Kubler, Andre; Gil-Santana, Leonardo; Fukutani, Kiyoshi F.; Scanga, Charles A.; Flynn, Jo Anne L.; Jackson, Sharon H.; Wilkinson, Katalin A.; Bishai, William R.; Sher, Alan; Wilkinson, Robert J.; Andrade, Bruno B. / Mycobacterium tuberculosis induction of heme oxygenase-1 expression is dependent on oxidative stress and reflects treatment outcomes.

In: Frontiers in Immunology, Vol. 8, No. MAY, 542, 12.05.2017.

Research output: Contribution to journalArticle

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