Resistance to Plasmodium falciparum in sickle cell trait erythrocytes is driven by oxygen-dependent growth inhibition
Resistance to Plasmodium falciparum in sickle cell trait erythrocytes is driven by oxygen-dependent growth inhibition
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DOI：
10.1073/pnas.1804388115
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发表时间：
2018-07-10
影响因子：
11.1
通讯作者：
Duraisingh, Manoj T.
中科院分区：
文献类型：
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作者：
Archer, Natasha M.;Petersen, Nicole;Duraisingh, Manoj T.
镰状细胞特性(AS)对致死性恶性疟疾具有部分保护作用。对此提出了多种机制，最近的焦点是寄生虫感染的红细胞(RBCs)的异常细胞黏附。这里，我们通过详细的时间映射来研究AS保护的机制基础。我们发现，AS红细胞中的寄生虫维持在低氧浓度时，在DNA复制之前的细胞内生长中期的特定阶段停滞。我们证明，镰状血红蛋白(HBS)的聚合是导致红细胞内恶性疟原虫生长停滞的原因，在一氧化碳(一种气态抗病毒剂)的存在下，恢复了正常的血红蛋白消化和生长。生长抑制和隔离的模型显示，HBS聚合诱导的细胞黏附后的生长抑制是在AS患者的疟疾感染中观察到的寄生虫密度降低的关键驱动因素。我们得出结论，AS的保护作用很大程度上来自于有效地将感染的红细胞隔离到缺氧的微循环中。
Sickle cell trait (AS) confers partial protection against lethal Plasmodium falciparum malaria. Multiple mechanisms for this have been proposed, with a recent focus on aberrant cytoadherence of parasite-infected red blood cells (RBCs). Here we investigate the mechanistic basis of AS protection through detailed temporal mapping. We find that parasites in AS RBCs maintained at low oxygen concentrations stall at a specific stage in the middle of intracellular growth before DNA replication. We demonstrate that polymerization of sickle hemoglobin (HbS) is responsible for this growth arrest of intraerythrocytic P. falciparum parasites, with normal hemoglobin digestion and growth restored in the presence of carbon monoxide, a gaseous antisickling agent. Modeling of growth inhibition and sequestration revealed that HbS polymerization-induced growth inhibition following cytoadherence is the critical driver of the reduced parasite densities observed in malaria infections of individuals with AS. We conclude that the protective effect of AS derives largely from effective sequestration of infected RBCs into the hypoxic microcirculation.