Heme Catabolism by Heme Oxygenase-1 Confers Host Resistance to Mycobacterium Infection
Open accessAbstract
Heme oxygenases (HO) catalyze the rate-limiting step of heme degradation. The cytoprotective action of the inducible HO-1 isoform, encoded by the Hmox1 gene, 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 intravenous Mycobacterium avium infection, 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 with Mycobacterium tuberculosis. The protective effect of HO-1 acts independently of adaptive immunity, as revealed in M. avium-infected Hmox1−/−versus Hmox1+/+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 to M. avium-infected wild-type Mϕ in vitro or to mice in vivo. In conclusion, HO-1 prevents the cytotoxic effect of heme in Mϕ, contributing critically to host resistance to Mycobacterium infection.
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Heme oxygenase-1 (HO-1), induced in activated macrophages, exerts tissue protection by limiting accumulation of pro-oxidant and cytotoxic heme molecules.
“the enzyme heme oxygenase-1 (HO-1), which is induced in activated macrophages, exerts tissue protection by limiting the accumulation of pro-oxidant and cytotoxic heme molecules (104).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [104]
The cytoprotective effect of CO likely prevents infected macrophages from undergoing necroptosis, supporting granuloma formation and resistance to Mycobacteria.
“While it is not clear whether this effect is mediated via CO and/or other products of heme catabolism, such as biliverdin and Fe, it is likely that the cytoprotective effect of CO [172] prevents infected Mø from undergoing programmed cell death by necroptosis [173].This cytoprotective effect should support granuloma formation and hence resistance to Mycobacteria [170,171].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [170]
Heme catabolism by HO-1 supports resistance to intracellular bacteria, as suggested for Mycobacteria infection in mice.
“Heme catabolism by HO-1 also supports resistance to intracellular bacteria, as suggested for Mycobacteria infection in mice [170,171].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [170]
CO regulates Mø polarization, limiting tissue damage associated with Mø activation in infectious diseases.
“This suggests that CO regulates Mø polarization, in a manner that should limit the extent of tissue damage associated with Mø activation, in the context of infectious diseases, such as sepsis driven by polymicrobial infection [190] as well as severe forms of malaria [103-106], tuberculosis [47,170,226], or trypanosomiasis [227].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [170]
HO-1 is central to support resistance to Mycobacteria infection in mice.
“The recent finding that HO-1 is central to support resistance to Mycobacteria infection in mice suggests that targeting heme catabolism may be used therapeutically against tuberculosis [170].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [170]
Targeting heme catabolism may be used therapeutically against tuberculosis.
“The recent finding that HO-1 is central to support resistance to Mycobacteria infection in mice suggests that targeting heme catabolism may be used therapeutically against tuberculosis [170].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [170]
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- Authors
- Silva-Gomes, S., Appelberg, R., Larsen, R., Soares, M. P., & Gomes, M. S.
- Affiliations
- Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
- Universidade do Porto (PT)
- Instituto Gulbenkian de Ciência (PT)
- Venue
- Infection and Immunity
- Publisher
- American Society for Microbiology
- Published
- 2013-07
- Volume
- 81
- Issue
- 7
- Pages
- 2536-2545
- ISSN
- 0019-9567 (ISSN-L)
- 1098-5522
- PMC
- PMC3697604
- OpenAlex
- W2156217650
- Cited by
- 85
- References
- 62
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 2 · 2022: 5 · 2021: 12 · 2020: 8 · 2019: 3 · 2018: 7 · 2017: 5 · 2016: 9 · 2015: 12 · 2014: 6 · 2013: 3
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Infection and Immunity (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Funders
- Universidade do Minho
- Fundação para a Ciência e a Tecnologia (SFRH/BPD/25436/2005)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- heme oxygenase-1, heme degradation, Mycobacterium avium, Mycobacterium tuberculosis, macrophages, granulomatous inflammation, SCID mice, aerosol infection, systemic infection
- MeSH terms
- Animals, Cells, Cultured, Granuloma, Heme, Liver, Lung, Macrophages, Membrane Proteins, Mycobacterium avium, Mycobacterium tuberculosis, Tuberculosis, Mice, SCID, Cell Death, Oxidative Stress, Microbial Viability, Mice, Heme Oxygenase-1, Bacterial Load, Disease Resistance
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