Abstract
ABSTRACTHeme 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.
Highlights
Heme oxygenase-1 (HO-1) is a stress response antioxidant enzyme which catalyzes the degradation of heme released during inflammation
When given to animals by daily intraperitoneal injection beginning on the same day as aerosol M. tuberculosis infection (Fig. 1A, protocol 1), SnPPIX induced a highly significant reduction in pulmonary bacterial load that was evident at 6 weeks but not 3 weeks postinfection (Fig. 1B)
This suggested to us that the delay in efficacy of SnPPIX on murine M. tuberculosis infection might be due to a requirement for T lymphocyte cooperation in the activity of the HO-1 inhibitor
Summary
Heme oxygenase-1 (HO-1) is a stress response antioxidant enzyme which catalyzes the degradation of heme released during inflammation. When given to animals by daily intraperitoneal injection beginning on the same day as aerosol M. tuberculosis infection (Fig. 1A, protocol 1), SnPPIX induced a highly significant reduction in pulmonary bacterial load that was evident at 6 weeks but not 3 weeks postinfection (wpi) (Fig. 1B). In parallel experiments in which animals were euthanized at 2 weeks after treatment initiation, SnPPIX-treated infected TCR-␣Ϫ/Ϫ mice displayed bacterial loads indistinguishable from those in untreated TCR-␣Ϫ/Ϫ animals, while WT animals treated with the compound showed a highly significant reduction in mycobacterial burden compared to untreated control mice (Fig. 1E).
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