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 journalArticlepeer-review

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

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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