Mycobacterium tuberculosis Induction of Heme Oxygenase-1 Expression Is Dependent on Oxidative Stress and Reflects Treatment Outcomes

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.

Changes in inflammatory protein and lipid mediator profiles persist after antitubercular treatment of pulmonary and extrapulmonary tuberculosis: A prospective cohort study

“…A number of prospective studies have previously reported changes in biomarker levels during antitubercular treatment in either pulmonary or extrapulmonary TB cases [15,30,33,35,37,[39][40][41][49][50][51]. Our study adds to the current knowledge in the field by directly comparing these changes between PTB and EPTB disease forms while focusing on both lipid mediators and inflammatory cytokines.…”

“…Studying plasma biomarkers in the context of TB may provide important insights into diagnosis, treatment efficacy and also disease pathogenesis [33]. Several prior studies have reported concentrations of cytokines, chemokines, acute phase proteins and lipid mediators in populations of pulmonary TB patients [30,[34][35][36][37][38][39][40][41], but less is known about extrapulmonary infection [42][43][44]. Here, we performed multiparametric analyses of plasma concentrations of several inflammatory cytokines, soluble cytokine receptors, receptor ligands, alongside with lipid mediators in a large set of active TB patients with pulmonary or extrapulmonary disease to characterize the systemic inflammatory profile of this disease.…”

“…Baseline and post treatment plasma samples originated from persons with signs and symptoms indicative of active TB and who were HIV-uninfected and who were not undertaking antitubercular therapy or healthy controls that were enrolled into a prospective clinical protocol to assess response to chemotherapy (NCT01071603) conducted at the Henan Chest Hospital (HCH) in Zhengzhou, China from 2010 to 2012, as described previously [6,15,16]. Individuals with pulmonary tuberculosis (PTB) were similar to those presenting with extra pulmonary tuberculosis (EPTB) with regard to age (median [IQR] in years: 27 [23-44.7] vs. 27 [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36], respectively; P = 0.1933; Supplemental Table 1) and gender (P = 0.4916, Table S1), with higher frequency of male individuals (61.7% vs. 52% vs. respectively).…”

“…In addition to mycobacterial loads in sputum, radiographic disease extension has been used by our group and others as a potential parameter of TB disease severity [19,26,29,30]. We next stratified the PTB patients into mild and severe clinical subgroups based on AFB smear status (positive vs. negative) and on radiographic extension of lung lesions (unilateral vs. bilateral) and compared the inflammatory signatures (Fig.…”

Host heme oxygenase‐1: Friend or foe in tackling pathogens?

“…Interestingly, the plasma level of HMOX1 was proposed as a biomarker capable of differentiating patients with active disease from those with latent infection or those who have undergone treatment against TB . The correlation of HMOX1 expression with TB disease was also demonstrated in various animal models such as rabbits, mice, and primates . Nevertheless, more studies are required to delineate the role of HMOX1 in the pathogenesis of mycobacterial infections.…”