Heme Catabolism by Heme Oxygenase-1 Confers Host Resistance to Mycobacterium Infection

Abstract

ABSTRACTHeme oxygenases (HO) catalyze the rate-limiting step of heme degradation. The cytoprotective action of the inducible HO-1 isoform, encoded by theHmox1gene, is required for host protection against systemic infections. Here we report that upregulation of HO-1 expression in macrophages (Mϕ) is strictly required for protection against mycobacterial infection in mice. HO-1-deficient (Hmox1−/−) mice are more susceptible to intravenousMycobacterium aviuminfection, failing to mount a protective granulomatous response and developing higher pathogen loads, than infected wild-type (Hmox1+/+) controls. Furthermore,Hmox1−/−mice also develop higher pathogen loads and ultimately succumb when challenged with a low-dose aerosol infection withMycobacterium tuberculosis. The protective effect of HO-1 acts independently of adaptive immunity, as revealed inM. avium-infectedHmox1−/−versusHmox1+/+SCID mice lacking mature B and T cells. In the absence of HO-1, heme accumulation acts as a cytotoxic pro-oxidant in infected Mϕ, an effect mimicked by exogenous heme administration toM. avium-infected wild-type Mϕin vitroor to micein vivo. In conclusion, HO-1 prevents the cytotoxic effect of heme in Mϕ, contributing critically to host resistance toMycobacteriuminfection.