Ferreira Ana, Balla József, Jeney Viktória, Balla György, Soares Miguel P
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
J Mol Med (Berl). 2008 Oct;86(10):1097-111. doi: 10.1007/s00109-008-0368-5. Epub 2008 Jul 19.
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.
疟疾是由疟原虫感染引起的疾病，在所谓的不发达国家，它是贫困地区的地方病。恶性疟原虫是撒哈拉以南国家主要的感染性疟原虫物种，可引发严重疟疾的发展，包括脑型疟疾，这是一种神经综合征，每年导致超过100万（<5岁）儿童死亡。迄今为止，根除疟原虫感染，尤其是其致命后果的尝试均未成功。利用成熟的疟疾感染啮齿动物模型，我们发现疟原虫感染宿主的存活严格依赖于宿主上调血红素加氧酶-1（由基因Hmox1编码的HO-1）表达的能力。HO-1是一种应激反应酶，它通过释放铁并产生气体一氧化碳（CO）的反应，将游离血红素分解为胆绿素。HO-1通过血红素分解产生CO可预防脑型疟疾的发作。CO的保护作用是通过其与疟原虫感染血液阶段从受感染红细胞释放的游离血红蛋白（Hb）结合来介导的。CO与游离Hb的结合可防止血红素释放，从而防止游离血红素的产生，我们发现游离血红素在脑型疟疾的发病机制中起核心作用。在此，我们将探讨包括HO-1表达在内的防止游离血红素有害影响的防御机制如何影响疟原虫感染的病理结果，以及这些机制如何用于治疗以抑制其致命后果。
