Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria
Abstract
Cerebral malaria claims more than 1 million lives per year. We report that heme oxygenase-1 (HO-1, encoded by Hmox1) prevents the development of experimental cerebral malaria (ECM). BALB/c mice infected with Plasmodium berghei ANKA upregulated HO-1 expression and activity and did not develop ECM. Deletion of Hmox1 and inhibition of HO activity increased ECM incidence to 83% and 78%, respectively. HO-1 upregulation was lower in infected C57BL/6 compared to BALB/c mice, and all infected C57BL/6 mice developed ECM (100% incidence). Pharmacological induction of HO-1 and exposure to the end-product of HO-1 activity, carbon monoxide (CO), reduced ECM incidence in C57BL/6 mice to 10% and 0%, respectively. Whereas neither HO-1 nor CO affected parasitemia, both prevented blood-brain barrier (BBB) disruption, brain microvasculature congestion and neuroinflammation, including CD8(+) T-cell brain sequestration. These effects were mediated by the binding of CO to hemoglobin, preventing hemoglobin oxidation and the generation of free heme, a molecule that triggers ECM pathogenesis.
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Labile heme plays a central role in the pathogenesis of severe forms of malaria and severe sepsis in mice.
“Labile heme plays a central role in the pathogenesis of severe forms of malaria as well as severe sepsis in mice [103,105,190].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [105]
The cytotoxic effect of labile heme promotes tissue damage and compromises disease tolerance to malaria and severe sepsis.
“Presumably, it is this cytotoxic effect that promotes tissue damage and hence compromises disease tolerance to malaria and severe sepsis [103,105,190].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [105]
Labile heme impairs disease tolerance to systemic infections, as its pathogenic effect can be dissociated from host pathogen burden.
“The pathogenic effect of labile heme can be dissociated from the host's pathogen burden [103,105,190], suggesting that labile heme impairs disease tolerance to these systemic infections.”
From The Iron age of host–microbe interactions (2015) · cites this paper as [105]
The pathogenic effects of extracellular hemoglobin and labile heme are countered by adaptive responses converging on heme catabolism by HO-1, providing tissue damage control and disease tolerance to systemic infections.
“The pathogenic effects exerted by extracellular hemoglobin and labile heme are countered by adaptive responses that converge at the level of heme catabolism by HO-1 [38,219], providing tissue damage control and disease tolerance to systemic infections [103,105,106] (Fig 4).”
From The Iron age of host–microbe interactions (2015) · cites this paper as [105]
CO produced via heme catabolism by HO-1 confers disease tolerance to systemic infections, as demonstrated for malaria.
“The gasotransmitter CO, produced via heme catabolism by HO-1, also confers disease tolerance to systemic infections, as demonstrated for malaria [105].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [105]
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 [105]
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- Authors
- Pamplona, A., Ferreira, A., Balla, J., Jeney, V., Balla, G., Epiphanio, S., Chora, Â., Rodrigues, C. D., Gregoire, I. P., Cunha-Rodrigues, M., Portugal, S., Soares, M. P., & Mota, M. M.
- Affiliations
- University of Lisbon (PT)
- Instituto Gulbenkian de Ciência (PT)
- University of Debrecen (HU)
- Corresponding author
- Soares, Miguel P
- Mota, Maria M
- ORCID
- Venue
- Nature Medicine
- Published
- 2007-05-13
- Volume
- 13
- Issue
- 6
- Pages
- 703-710
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2021650047
- Cited by
- 560
- References
- 42
- Citations by year
- 2026: 16 · 2025: 28 · 2024: 15 · 2023: 23 · 2022: 38 · 2021: 25 · 2020: 29 · 2019: 28 · 2018: 26 · 2017: 23 · 2016: 35 · 2015: 31 · 2014: 28 · 2013: 41 · 2012: 39
- FWCI
- 14.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Universidade de Lisboa
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- heme oxygenase-1, carbon monoxide, cerebral malaria, Plasmodium berghei ANKA, blood-brain barrier disruption, neuroinflammation, hemoglobin oxidation, free heme, strain-dependent susceptibility, neuroprotection
- MeSH terms
- Animals, Carbon Monoxide, Disease Models, Animal, Heme, Mice, Inbred BALB C, Mice, Inbred C57BL, Plasmodium berghei, Mice, SCID, Malaria, Cerebral, Mice, Knockout, Mice, Heme Oxygenase-1
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