Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria.
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.
Pamplona
Ana
A
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
Ferreira
Ana
A
Balla
József
J
Jeney
Viktória
V
Balla
György
G
Epiphanio
Sabrina
S
Chora
Angelo
A
Rodrigues
Cristina D
CD
Gregoire
Isabel Pombo
IP
Cunha-Rodrigues
Margarida
M
Portugal
Silvia
S
Soares
Miguel P
MP
Mota
Maria M
MM
D000818:Animals; D002248:Carbon Monoxide / Q000502:physiology*; D004195:Disease Models, Animal; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016779:Malaria, Cerebral / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D010962:Plasmodium berghei
D006418:Heme; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1