A central role for free heme in the pathogenesis of severe malaria: the missing link?

@article{citeulike:3035625, abstract = {Malaria, the disease caused by Plasmodium infection, is endemic to poverty in so-called underdeveloped countries. Plasmodium falciparum, the main infectious Plasmodium species in sub-Saharan countries, can trigger the development of severe malaria, including cerebral malaria, a neurological syndrome that claims the lives of more than one million children (<5 years old) per year. Attempts to eradicate Plasmodium infection, and in particular its lethal outcomes, have so far been unsuccessful. Using well-established rodent models of malaria infection, we found that survival of a Plasmodium-infected host is strictly dependent on the host's ability to up-regulate the expression of heme oxygenase-1 (HO-1 encoded by the gene Hmox1). HO-1 is a stress-responsive enzyme that catabolizes free heme into biliverdin, via a reaction that releases Fe and generates the gas carbon monoxide (CO). Generation of CO through heme catabolism by HO-1 prevents the onset of cerebral malaria. The protective effect of CO is mediated via its binding to cell-free hemoglobin (Hb) released from infected red blood cells during the blood stage of Plasmodium infection. Binding of CO to cell-free Hb prevents heme release and thus generation of free heme, which we found to play a central role in the pathogenesis of cerebral malaria. We will address hereby how defense mechanisms that prevent the deleterious effects of free heme, including the expression of HO-1, impact on the pathologic outcome of Plasmodium infection and how these may be used therapeutically to suppress its lethal outcomes.}, address = {Instituto Gulbenkian de Ci\^{e}ncia, 2780-156, Oeiras, Portugal.}, author = {Ferreira, Ana and Balla, J\'{o}zsef and Jeney, Vikt\'{o}ria and Balla, Gy\"{o}rgy and Soares, Miguel P. }, citeulike-article-id = {3035625}, doi = {http://dx.doi.org/10.1007/s00109-008-0368-5}, issn = {0946-2716}, journal = {Journal of molecular medicine (Berlin, Germany)}, keywords = {malaria, pathogenesis}, month = {July}, posted-at = {2008-07-23 03:27:21}, priority = {2}, title = {A central role for free heme in the pathogenesis of severe malaria: the missing link?}, url = {http://dx.doi.org/10.1007/s00109-008-0368-5}, year = {2008} }

TY - JOUR ID - citeulike:3035625 L3 - citeulike-article-id:3035625 TI - A central role for free heme in the pathogenesis of severe malaria: the missing link? JF - Journal of molecular medicine (Berlin, Germany) AD - Instituto Gulbenkian de Ciência, 2780-156, Oeiras, Portugal. SN - 0946-2716 N2 - Malaria, the disease caused by Plasmodium infection, is endemic to poverty in so-called underdeveloped countries. Plasmodium falciparum, the main infectious Plasmodium species in sub-Saharan countries, can trigger the development of severe malaria, including cerebral malaria, a neurological syndrome that claims the lives of more than one million children (<5 years old) per year. Attempts to eradicate Plasmodium infection, and in particular its lethal outcomes, have so far been unsuccessful. Using well-established rodent models of malaria infection, we found that survival of a Plasmodium-infected host is strictly dependent on the host's ability to up-regulate the expression of heme oxygenase-1 (HO-1 encoded by the gene Hmox1). HO-1 is a stress-responsive enzyme that catabolizes free heme into biliverdin, via a reaction that releases Fe and generates the gas carbon monoxide (CO). Generation of CO through heme catabolism by HO-1 prevents the onset of cerebral malaria. The protective effect of CO is mediated via its binding to cell-free hemoglobin (Hb) released from infected red blood cells during the blood stage of Plasmodium infection. Binding of CO to cell-free Hb prevents heme release and thus generation of free heme, which we found to play a central role in the pathogenesis of cerebral malaria. We will address hereby how defense mechanisms that prevent the deleterious effects of free heme, including the expression of HO-1, impact on the pathologic outcome of Plasmodium infection and how these may be used therapeutically to suppress its lethal outcomes. KW - malaria KW - pathogenesis AU - Ferreira, Ana AU - Balla, József AU - Jeney, Viktória AU - Balla, György AU - Soares, Miguel PY - 2008/07/19/ UR - http://dx.doi.org/10.1007/s00109-008-0368-5 ER -