Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses Mycobacterium tuberculosis Infection In Vivo by a Mechanism Dependent on T Lymphocytes

Abstract

Heme oxygenase-1 (HO-1) is a stress response antioxidant enzyme which catalyzes the degradation of heme released during inflammation. HO-1 expression is upregulated in both experimental and human Mycobacterium tuberculosis infection, and in patients it is a biomarker of active disease. Whether the enzyme plays a protective versus pathogenic role in tuberculosis has been the subject of debate. To address this controversy, we administered tin protoporphyrin IX (SnPPIX), a well-characterized HO-1 enzymatic inhibitor, to mice during acute M. tuberculosis infection. These SnPPIX-treated animals displayed a substantial reduction in pulmonary bacterial loads comparable to that achieved following conventional antibiotic therapy. Moreover, when administered adjunctively with antimycobacterial drugs, the HO-1 inhibitor markedly enhanced and accelerated pathogen clearance. Interestingly, both the pulmonary induction of HO-1 expression and the efficacy of SnPPIX treatment in reducing bacterial burden were dependent on the presence of host T lymphocytes. Although M. tuberculosis expresses its own heme-degrading enzyme, SnPPIX failed to inhibit its enzymatic activity or significantly restrict bacterial growth in liquid culture. Together, the above findings reveal mammalian HO-1 as a potential target for host-directed monotherapy and adjunctive therapy of tuberculosis and identify the immune response as a critical regulator of this function.

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

“…In agreement with a recent study from our group (30), we found that HO-1 expression in both lungs and serum significantly increased following aerosol infection with Mtb (Figure 1B). Initiation of ATT reduced HO-1 induction, with concentrations substantially falling in the serum of mice receiving the antimicrobials compared to untreated animals (Figure 1B).…”

Microanatomic Distribution of Myeloid Heme Oxygenase-1 Protects against Free Radical-Mediated Immunopathology in Human Tuberculosis

“…In addition, our myeloid-specific knockout mice, which exhibit no signs of abnormality ( Tzima et al., 2009 ), were more susceptible to Mtb infection with significantly increased bacterial burden and reduced survival. In contrast, it was reported that pharmacological inhibition of HO-1 ( Costa et al., 2016 , Scharn et al., 2016 ) results in reduced Mtb burden, suggesting that HO-1 promotes TB. However, we view these findings as inconclusive, since pharmacological inhibition of HO-1 had no effect on the survival of Mtb -infected mice ( Costa et al., 2016 ), suggesting that other factors such as HO-1-independent T cell receptor mechanisms may be involved.…”

“…Furthermore, HO-1 levels in plasma were reported to be inversely correlated with the levels of matrix metalloproteinases, which contribute to tissue destruction in TB ( Andrade et al., 2015 , Salgame, 2011 ). More recently, studies have challenged the beneficial role of HO-1 in TB disease, reporting that pharmacological inhibition of HO-1 in mice leads to a decrease in Mtb burden ( Costa et al., 2016 , Scharn et al., 2016 ). These conflicting findings, in addition to the fact that the essentiality of HO-1 in humans and mice varies significantly, represent a substantial gap in our understanding of the role of HO-1 in TB.…”

Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients

“…HO-1, encoded by HMOX-1, is an inducible cytoprotective enzyme that catalyzes the oxidative degradation of heme into equimolar ratios of iron, carbon monoxide, and bilirubin (43). Although the transcript, protein, and activity levels of HO-1 are upregulated in response to M. tuberculosis infection, whether HO-1 has a protective or pathogenic role in TB remains controversial (17,34,(44)(45)(46)(47). In support of our findings, several reports have shown that pharmacological HO-1 inhibition decreases M. tuberculosis and Mycobacterium abscessus burden in vivo (44) and in vitro (34,45).…”

“…Although the transcript, protein, and activity levels of HO-1 are upregulated in response to M. tuberculosis infection, whether HO-1 has a protective or pathogenic role in TB remains controversial (17,34,(44)(45)(46)(47). In support of our findings, several reports have shown that pharmacological HO-1 inhibition decreases M. tuberculosis and Mycobacterium abscessus burden in vivo (44) and in vitro (34,45). Conversely, others have shown that HO-1 is required to control M. tuberculosis and Mycobacterium avium infections in mice (17,46,47).…”