Anti-CD81 but not anti-SR-BI blocks Plasmodium falciparum liver infection in a humanized mouse model
Anti-CD81 but not anti-SR-BI blocks Plasmodium falciparum liver infection in a humanized mouse model
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DOI：
10.1093/jac/dkv019
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发表时间：
2015-06-01
影响因子：
5.2
通讯作者：
Meuleman, Philip
中科院分区：
文献类型：
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作者：
Foquet, Lander;Hermsen, Cornelus C.;Meuleman, Philip
目的：恶性疟原虫子孢子，通过受感染的按蚊吸血而沉积在皮肤中，穿过皮肤毛细血管的内皮并行进到肝脏，在那里它们穿过枯否细胞和肝细胞，最终侵入少量的肝细胞。在肝细胞中，子孢子复制、分化并产生大量裂殖子，裂殖子被释放到血流中，在血流中它们侵入红细胞，从而启动有症状的血液阶段。利用体外系统和啮齿动物模型，已经表明肝细胞受体CD 81和清道夫受体B I类（SR-BI）在子孢子侵入过程中起关键作用。我们想评估这两个进入因素是否是真正的药物目标，为预防恶性疟原虫infection in humans.Methods：免疫缺陷小鼠的肝脏主要是重新填充人肝细胞进行治疗与单克隆抗体阻断CD 81或SR-BI 1天前，与受感染的蚊子的挑战。结果：在人肝嵌合体小鼠中，抗CD 81的抗体完全阻断了恶性疟原虫子孢子的侵入，而SR-BI特异性单克隆抗体对体内感染没有影响。结论：这些观察结果证实了CD 81在肝期疟疾中的作用，并对SR-BI的作用提出了质疑。CD 81可能是一个有价值的疟疾防治药物靶点。
Objectives: Plasmodium falciparum sporozoites, deposited in the skin by infected Anopheles mosquitoes taking a blood meal, cross the endothelium of skin capillaries and travel to the liver where they traverse Kupffer cells and hepatocytes to finally invade a small number of the latter. In hepatocytes, sporozoites replicate, differentiate and give rise to large numbers of merozoites that are released into the bloodstream where they invade red blood cells, thus initiating the symptomatic blood stage. Using in vitro systems and rodent models, it has been shown that the hepatocyte receptors CD81 and scavenger receptor type B class I (SR-BI) play a pivotal role during sporozoite invasion. We wanted to evaluate whether these two entry factors are genuine drug targets for the prevention of P. falciparum infection in humans.Methods: Immunodeficient mice of which the liver is largely repopulated by human hepatocytes were treated with monoclonal antibodies blocking either CD81 or SR-BI 1 day prior to challenge with infected mosquitoes. P. falciparum infection of the liver was demonstrated using a qPCR assay.Results: In human liver chimeric mice, an antibody directed against CD81 completely blocked P. falciparum sporozoite invasion while SR-BI-specific monoclonal antibodies did not influence in vivo infection.Conclusions: These observations confirm the role of CD81 in liver-stage malaria and question that of SR-BI. CD81 might be a valuable drug target for the prevention of malaria.