Heme oxygenase-1 affords protection against noncerebral forms of severe malaria
Open accessAbstract
Infection by Plasmodium , the causative agent of malaria, is associated with hemolysis and therefore with release of hemoglobin from RBC. Under inflammatory conditions, cell-free hemoglobin can be oxidized, releasing its heme prosthetic groups and producing deleterious free heme. Here we demonstrate that survival of a Plasmodium -infected host relies strictly on its ability to prevent the cytotoxic effects of free heme via the expression of the heme-catabolyzing enzyme heme oxygenase-1 (HO-1; encoded by the Hmox1 gene). When infected with Plasmodium chabaudi chabaudi ( Pcc ), wild-type ( Hmox1 +/+ ) BALB/c mice resolved infection and restored homeostasis thereafter (0% lethality). In contrast, HO-1 deficient ( Hmox1 −/− ) BALB/c mice developed a lethal form of hepatic failure (100% lethality), similar to the one occurring in Pcc -infected DBA/2 mice (75% lethality). Expression of HO-1 suppresses the pro-oxidant effects of free heme, preventing it from sensitizing hepatocytes to undergo TNF-mediated programmed cell death by apoptosis. This cytoprotective effect, which inhibits the development of hepatic failure in Pcc -infected mice without interfering with pathogen burden, is mimicked by pharmacological antioxidants such as N-acetylcysteine (NAC). When administered therapeutically, i.e., after Pcc infection, NAC suppressed the development of hepatic failure in Pcc -infected DBA/2 mice (0% lethality), without interfering with pathogen burden. In conclusion, we describe a mechanism of host defense against Plasmodium infection, based on tissue cytoprotection against free heme and limiting disease severity irrespectively of parasite burden.
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HO-1 induction reduces the severity of experimental malaria.
“Accordingly, HO-1 induction limits the morbidity of experimental malaria (Seixas et al., 2009).”
From Iron in infection and immunity (2013) · cites this paper as Seixas et al., 2009
Heme sensitizes cells to undergo apoptosis, as indicated by partial suppression of heme sensitization by caspase inhibition.
“Heme sensitization to programmed cell death is partially suppressed by pharmacologic inhibition of caspases [106,107], indicating that heme sensitizes cells to undergo apoptosis [216].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [106]
Once released from hemoglobin, labile heme becomes pro-oxidant and cytotoxic.
“Once released from hemoglobin, the redox activity of labile heme becomes pro-oxidant and cytotoxic [38,106,107,190] (Fig 4).”
From The Iron age of host–microbe interactions (2015) · cites this paper as [106]
Labile heme sensitizes parenchyma cells to undergo programmed cell death in response to proinflammatory cytokines such as TNF, as well as Fas, ROS, and RNS.
“Briefly, labile heme sensitizes parenchyma cells to undergo programmed cell death in response to proinflammatory cytokines such as TNF [106] as well as other agonists such as Fas as well as ROS and RNS [38,190].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [106]
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 [106]
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 [106]
The protective effects of FTH do not interfere with host pathogen burden, illustrating that regulation of host Fe metabolism confers disease tolerance to infection.
“The protective effects of FTH do not interfere with host pathogen burden, illustrating further how regulation of host Fe metabolism confers disease tolerance to infection [103,106,190].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [106]
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Self-citation
- Authors
- Seixas, E., Gozzelino, R., Chora, Â., Ferreira, A., Silva, G., Larsen, R., Rebelo, S., Penido, C., Smith, N. R., Coutinho, A., & Soares, M. P.
- Affiliations
- Instituto Gulbenkian de Ciência (PT)
- Massachusetts General Hospital (US)
- Instituto Gulbenkian de Ciência, Oeiras, Portugal and
- Corresponding author
- Soares, Miguel P.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-09-15
- Volume
- 106
- Issue
- 37
- Pages
- 15837-15842
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2728109
- OpenAlex
- W2158040122
- Cited by
- 275
- References
- 5
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 10 · 2023: 9 · 2022: 14 · 2021: 13 · 2020: 17 · 2019: 12 · 2018: 24 · 2017: 18 · 2016: 18 · 2015: 17 · 2014: 21 · 2013: 23 · 2012: 25
- FWCI
- 8.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Universidade Federal do Rio de Janeiro
- 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, severe malaria, Plasmodium chabaudi chabaudi, free heme, free hemoglobin, liver failure, hepatocyte apoptosis, N-acetylcysteine, antioxidant therapy, host defense, hemolysis, DBA/2 mice
- MeSH terms
- Acetylcysteine, Animals, Antioxidants, Heme, Malaria, Mice, Inbred BALB C, Mice, Inbred DBA, Tumor Necrosis Factor-alpha, Gene Expression, Mice, SCID, Plasmodium chabaudi, Liver Failure, Apoptosis, Transplantation Chimera, Mice, Knockout, Oxidative Stress, Hepatocytes, Mice, Heme Oxygenase-1
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