Malaria Vaccine Development Laboratory, Institut Pasteur, Paris, France.
PLoS One. 2011 Mar 31;6(3):e18045. doi: 10.1371/journal.pone.0018045.
It has been shown previously that it is possible to obtain growth of Plasmodium falciparum in human erythrocytes grafted in mice lacking adaptive immune responses by controlling, to a certain extent, innate defences with liposomes containing clodronate (clo-lip). However, the reproducibility of those models is limited, with only a proportion of animals supporting longstanding parasitemia, due to strong inflammation induced by P. falciparum. Optimisation of the model is much needed for the study of new anti-malarial drugs, drug combinations, and candidate vaccines.
MATERIALS/METHODS: We investigated the possibility of improving previous models by employing the intravenous route (IV) for delivery of both human erythrocytes (huRBC) and P. falciparum, instead of the intraperitoneal route (IP), by testing various immunosuppressive drugs that might help to control innate mouse defences, and by exploring the potential benefits of using immunodeficient mice with additional genetic defects, such as those with IL-2Rγ deficiency (NSG mice).
We demonstrate here the role of aging, of inosine and of the IL-2 receptor γ mutation in controlling P. falciparum induced inflammation. IV delivery of huRBC and P. falciparum in clo-lip treated NSG mice led to successful infection in 100% of inoculated mice, rapid rise of parasitemia to high levels (up to 40%), long-lasting parasitemia, and consistent results from mouse-to-mouse. Characteristics were closer to human infection than in previous models, with evidence of synchronisation, partial sequestration, and receptivity to various P. falciparum strains without preliminary adaptation. However, results show that a major IL-12p70 inflammatory response remains prevalent.
The combination of the NSG mouse, clodronate loaded liposomes, and IV delivery of huRBC has produced a reliable and more relevant model that better meets the needs of Malaria research.
先前已经表明，通过控制载有氯膦酸脂质体（clo-lip）的先天防御，在缺乏适应性免疫反应的小鼠中移植人红细胞，可以使恶性疟原虫（Plasmodium falciparum）生长。然而，由于恶性疟原虫引起的强烈炎症，这些模型的重现性有限，只有一部分动物支持长期的寄生虫血症。因此，对于新的抗疟药物、药物组合和候选疫苗的研究，非常需要对该模型进行优化。
材料/方法：我们通过静脉途径（IV）而不是腹腔途径（IP），来研究通过输送人红细胞（huRBC）和恶性疟原虫（P. falciparum），改善先前模型的可能性。我们测试了各种可能有助于控制先天的小鼠防御的免疫抑制药物，并探索了利用具有额外遗传缺陷的免疫缺陷小鼠（如缺乏白细胞介素 2 受体 γ（IL-2Rγ）的 NSG 小鼠）的潜在益处。
我们在这里证明了衰老、肌苷和白细胞介素 2 受体 γ 突变在控制恶性疟原虫诱导的炎症中的作用。在 clo-lip 处理的 NSG 小鼠中静脉注射 huRBC 和 P. falciparum ，导致 100%接种的小鼠成功感染，寄生虫血症迅速升高至高水平（高达 40%），寄生虫血症持续时间长，且从一只小鼠到另一只小鼠的结果一致。这些特征与人类感染更为接近，有同步、部分隔离和对各种恶性疟原虫株的易感性的证据，而无需预先适应。然而，结果表明，主要的白细胞介素 12p70 炎症反应仍然普遍存在。
NSG 小鼠、氯膦酸脂质体和 huRBC 的 IV 注射的组合产生了一种可靠且更相关的模型，更好地满足了疟疾研究的需求。
