Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, North Carolina, United States of America.
PLoS Pathog. 2013;9(5):e1003327. doi: 10.1371/journal.ppat.1003327. Epub 2013 May 16.
Plasmodium falciparum malaria kills over 500,000 children every year and has been a scourge of humans for millennia. Owing to the co-evolution of humans and P. falciparum parasites, the human genome is imprinted with polymorphisms that not only confer innate resistance to falciparum malaria, but also cause hemoglobinopathies. These genetic traits--including hemoglobin S (HbS), hemoglobin C (HbC), and α-thalassemia--are the most common monogenic human disorders and can confer remarkable degrees of protection from severe, life-threatening falciparum malaria in African children: the risk is reduced 70% by homozygous HbC and 90% by heterozygous HbS (sickle-cell trait). Importantly, this protection is principally present for severe disease and largely absent for P. falciparum infection, suggesting that these hemoglobinopathies specifically neutralize the parasite's in vivo mechanisms of pathogenesis. These hemoglobin variants thus represent a "natural experiment" to identify the cellular and molecular mechanisms by which P. falciparum produces clinical morbidity, which remain partially obscured due to the complexity of interactions between this parasite and its human host. Multiple lines of evidence support a restriction of parasite growth by various hemoglobinopathies, and recent data suggest this phenomenon may result from host microRNA interference with parasite metabolism. Multiple hemoglobinopathies mitigate the pathogenic potential of parasites by interfering with the export of P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of the host red blood cell. Few studies have investigated their effects upon the activation of the innate and adaptive immune systems, although recent murine studies suggest a role for heme oxygenase-1 in protection. Ultimately, the identification of mechanisms of protection and pathogenesis can inform future therapeutics and preventive measures. Hemoglobinopathies slice the "Gordian knot" of host and parasite interactions to confer malaria protection, and offer a translational model to identify the most critical mechanisms of P. falciparum pathogenesis.
恶性疟原虫疟疾每年导致超过 50 万儿童死亡，数千年来一直是人类的祸害。由于人类和恶性疟原虫寄生虫的共同进化，人类基因组中存在着多态性，这些多态性不仅赋予了对恶性疟原虫疟疾的先天抵抗力，还导致了血红蛋白病。这些遗传特征——包括血红蛋白 S（HbS）、血红蛋白 C（HbC）和α-地中海贫血——是最常见的单基因人类疾病，可以为非洲儿童提供对严重、危及生命的恶性疟原虫疟疾的显著程度的保护：纯合子 HbC 可降低 70%的风险，杂合子 HbS（镰状细胞特征）可降低 90%的风险。重要的是，这种保护主要存在于严重疾病中，而在恶性疟原虫感染中基本不存在，这表明这些血红蛋白病专门中和了寄生虫的体内发病机制。因此，这些血红蛋白变体代表了一个“自然实验”，可以确定恶性疟原虫产生临床发病率的细胞和分子机制，由于寄生虫与其人类宿主之间相互作用的复杂性，这些机制仍然部分不明确。多项证据支持各种血红蛋白病对寄生虫生长的限制，最近的数据表明，这种现象可能是由于宿主 microRNA 干扰寄生虫代谢所致。多种血红蛋白病通过干扰恶性疟原虫红细胞膜蛋白 1（PfEMP1）向宿主红细胞表面的输出，减轻寄生虫的致病潜力。很少有研究调查它们对固有和适应性免疫系统激活的影响，尽管最近的鼠类研究表明血红素加氧酶-1 在保护中起作用。最终，确定保护和发病机制的机制可以为未来的治疗和预防措施提供信息。血红蛋白病切割宿主和寄生虫相互作用的“戈尔迪之结”，为疟疾保护提供了一个转化模型，以确定恶性疟原虫发病机制的最关键机制。
