Sickle Hemoglobin Confers Tolerance to Plasmodium Infection
Sickle Hemoglobin Confers Tolerance to Plasmodium Infection
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DOI：
10.1016/j.cell.2011.03.049
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发表时间：
2011-04-29
期刊：
影响因子：
64.5
通讯作者：
Soares, Miguel P.
中科院分区：
文献类型：
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作者：
Ferreira, Ana;Marguti, Ivo;Soares, Miguel P.
镰状人类血红蛋白 (Hb) 为生活在疟疾流行区的个人提供了生存优势，疟疾是由疟原虫感染引起的疾病。如本文所证明的，表达镰状Hb的小鼠不会死于实验性脑型疟疾(ECM)。这种保护作用的发挥与寄生虫负载无关，表明镰状血红蛋白赋予宿主对疟原虫感染的耐受性。 Sickle Hb 通过涉及转录因子 NF-E2 相关因子 2 (Nrf2) 的机制诱导造血细胞中血红素加氧酶-1 (HO-1) 的表达。一氧化碳 (CO) 是 HO-1 血红素分解代谢的副产物，可防止疟原虫感染后循环游离血红素的进一步积累，从而抑制 ECM 的发病机制。此外，镰状Hb可抑制识别疟原虫表达的抗原的致病性CD8+T细胞的激活和/或扩增，这是一种不涉及Nrf2和/或HO-1的免疫调节作用。我们的研究结果提供了对镰状血红蛋白赋予宿主对严重疟疾耐受性的分子机制的深入了解。
Sickle human hemoglobin (Hb) confers a survival advantage to individuals living in endemic areas of malaria, the disease caused by Plasmodium infection. As demonstrated hereby, mice expressing sickle Hb do not succumb to experimental cerebral malaria (ECM). This protective effect is exerted irrespectively of parasite load, revealing that sickle Hb confers host tolerance to Plasmodium infection. Sickle Hb induces the expression of heme oxygenase-1 (HO-1) in hematopoietic cells, via a mechanism involving the transcription factor NF-E2-related factor 2 (Nrf2). Carbon monoxide (CO), a byproduct of heme catabolism by HO-1, prevents further accumulation of circulating free heme after Plasmodium infection, suppressing the pathogenesis of ECM. Moreover, sickle Hb inhibits activation and/or expansion of pathogenic CD8(+) T cells recognizing antigens expressed by Plasmodium, an immunoregulatory effect that does not involve Nrf2 and/or HO-1. Our findings provide insight into molecular mechanisms via which sickle Hb confers host tolerance to severe forms of malaria.