A Murine Model of falciparum-Malaria by In Vivo Selection of Competent Strains in Non-Myelodepleted Mice Engrafted with Human Erythrocytes
A Murine Model of falciparum-Malaria by In Vivo Selection of Competent Strains in Non-Myelodepleted Mice Engrafted with Human Erythrocytes
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DOI：
10.1371/journal.pone.0002252
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发表时间：
2008-05-21
期刊：
影响因子：
3.7
通讯作者：
Gargallo-Viola, Domingo
中科院分区：
文献类型：
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作者：
Angulo-Barturen, Inigo;Belen Jimenez-Diaz, Maria;Gargallo-Viola, Domingo
为了应对恶性疟原虫疟疾造成的全球威胁，迫切需要新的药物和疫苗。然而，没有实用的动物模型，因为恶性疟原虫几乎只感染人类红细胞。在这里，我们描述了一个可靠的恶性疟原虫疟疾小鼠模型，通过在体内产生的恶性疟原虫株，可以感染移植人红细胞的免疫缺陷小鼠。我们用从体外培养物中获得的恶性疟原虫感染移植有人红细胞的NODscid/β 2 m-/-小鼠。在明显清除后，我们获得了能够在移植的NODscid/β 2 m-/-小鼠的外周血中生长的恶性疟原虫分离株。在获得的分离株中，我们在体内扩增并建立分离株Pf 3D 7（0087/N9）作为模型开发的参考菌株。Pf 3D 7（0087/N9）在100%的静脉内感染的移植小鼠中引起生产性持续感染。由于通过依赖于外周血中寄生虫密度的机制选择性消除人红细胞，感染引起相对贫血。使用该模型，我们实施并验证了一种可重复的抗疟活性测定方法，可用于药物发现。因此，我们的研究结果表明，恶性疟原虫含有克隆，能够在移植人红细胞的小鼠中重复生长，而无需使用清髓性方法。
To counter the global threat caused by Plasmodium falciparum malaria, new drugs and vaccines are urgently needed. However, there are no practical animal models because P. falciparum infects human erythrocytes almost exclusively. Here we describe a reliable falciparum murine model of malaria by generating strains of P. falciparum in vivo that can infect immunodeficient mice engrafted with human erythrocytes. We infected NODscid/beta 2m-/- mice engrafted with human erythrocytes with P. falciparum obtained from in vitro cultures. After apparent clearance, we obtained isolates of P. falciparum able to grow in peripheral blood of engrafted NODscid/beta 2m-/- mice. Of the isolates obtained, we expanded in vivo and established the isolate Pf3D7(0087/N9) as a reference strain for model development. Pf3D7(0087/N9) caused productive persistent infections in 100% of engrafted mice infected intravenously. The infection caused a relative anemia due to selective elimination of human erythrocytes by a mechanism dependent on parasite density in peripheral blood. Using this model, we implemented and validated a reproducible assay of antimalarial activity useful for drug discovery. Thus, our results demonstrate that P. falciparum contains clones able to grow reproducibly in mice engrafted with human erythrocytes without the use of myeloablative methods.