Sacci John B, Alam Uzma, Douglas Donna, Lewis Jamie, Tyrrell D Lorne J, Azad Abdu F, Kneteman Norman M
Department of Microbiology and Immunology, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201, USA.
Int J Parasitol. 2006 Mar;36(3):353-60. doi: 10.1016/j.ijpara.2005.10.014.
The exoerythrocytic stage of Plasmodium falciparum has remained a difficult phase of the parasite life-cycle to study. The host and tissue specificity of the parasite requires the experimental infection of humans or non-human primates and subsequent surgical recovery of parasite-infected liver tissue to analyze this stage of the parasites development. This type of study is impossible in humans due to obvious ethical considerations and the cost and complexity in working with primate models has precluded their use for extensive studies of the exoerythrocytic stage. In this study we assessed, for the first time, the use of transgenic, chimeric mice containing functioning human hepatocytes as an alternative for modeling the in vivo interaction of P. falciparum parasites and human hepatocytes. Infection of these mice with P. falciparum sporozoites produced morphologically and antigenically mature liver stage schizonts containing merozoites capable of invading human red blood cells. Additionally, using microdissection, highly enriched P. falciparum liver stage parasites essentially free of hepatocyte contamination, were recovered for molecular studies. Our results establish a stable murine model for P. falciparum that will have a wide utility for assessing the biology of the parasite, potential anti-malarial chemotherapeutic agents and vaccine design.
恶性疟原虫的红细胞外期一直是该寄生虫生命周期中一个难以研究的阶段。该寄生虫的宿主和组织特异性要求对人类或非人类灵长类动物进行实验性感染，随后通过手术获取感染寄生虫的肝脏组织，以分析寄生虫发育的这一阶段。由于明显的伦理考量，这种研究在人类中是不可能进行的，而且使用灵长类动物模型的成本和复杂性使得它们无法用于对红细胞外期进行广泛研究。在本研究中，我们首次评估了使用含有功能性人类肝细胞的转基因嵌合小鼠作为模拟恶性疟原虫与人类肝细胞体内相互作用的替代模型。用恶性疟原虫子孢子感染这些小鼠后，产生了形态和抗原成熟的肝期裂殖体，其中含有能够侵入人类红细胞的裂殖子。此外，通过显微切割，获得了高度富集的、基本无肝细胞污染的恶性疟原虫肝期寄生虫，用于分子研究。我们的结果建立了一个稳定的恶性疟原虫小鼠模型，该模型在评估寄生虫生物学、潜在抗疟化疗药物和疫苗设计方面将具有广泛的用途。
