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.