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↵1E.S. and R.G. contributed equally to this work.
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Edited by Louis H. Miller, National Institutes of Health, Rockville, MD, and approved July 6, 2009 (received for review March 27, 2009)
Abstract
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.
Footnotes
- 2To whom correspondence should be addressed. E-mail: mpsoares{at}igc.gulbenkian.pt
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Author contributions: E.S., R.G., A. Chora, C.P., A. Coutinho, and M.P.S. designed research; E.S., R.G., A. Chora, A.F., G.S., R.L., S.R., C.P., and N.R.S. performed research; E.S., R.G., A. Chora, A.F., G.S., R.L., C.P., N.R.S., A. Coutinho, and M.P.S. analyzed data; and M.P.S. wrote the paper.
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Edited by Louis H. Miller, National Institutes of Health, Rockville, MD, and approved July 6, 2009
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Heme oxygenase-1 affords protection against noncerebral forms of severe malaria
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