Plasmodium falciparum Liver Stage Infection and Transition to Stable Blood Stage Infection in Liver-Humanized and Blood-Humanized FRGN KO Mice Enables Testing of Blood Stage Inhibitory Antibodies (Reticulocyte-Binding Protein Homolog 5) In Vivo
Plasmodium falciparum Liver Stage Infection and Transition to Stable Blood Stage Infection in Liver-Humanized and Blood-Humanized FRGN KO Mice Enables Testing of Blood Stage Inhibitory Antibodies (Reticulocyte-Binding Protein Homolog 5) In Vivo
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DOI：
10.3389/fimmu.2018.00524
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发表时间：
2018-03-14
影响因子：
7.3
通讯作者：
Kappe, Stefan H. I.
中科院分区：
文献类型：
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作者：
Foquet, Lander;Schafer, Carola;Kappe, Stefan H. I.
肝脏人源化小鼠模型的发明使得直接研究恶性疟原虫的红细胞前期阶段成为可能。相比之下，目前直接研究体内血液阶段感染的模型非常有限。小鼠血流的人源化可以通过频繁注射人红细胞（hRBC）来实现，并且是目前唯一用于在小动物模型中研究人类疟疾血液阶段感染的系统。感染主要通过直接注射恶性疟原虫感染的RBC来实现，但同样地，这种感染方式不模拟蚊子叮咬的自然感染途径，并且缺乏寄生虫从肝脏阶段感染到血液阶段感染的转变。在小动物模型中包括这些生命周期转变点对于测试治疗干预是相关的。为此，我们使用FRGN KO小鼠，其移植有人肝细胞，并在免疫调节下进行血液交换，以移植具有超过50% hRBC的动物。这些小鼠通过蚊子叮咬感染表达抗疟酶的恶性疟原虫的子孢子阶段，在感染后5-7天通过体内生物发光成像（IVIS）产生非侵入性可测量的肝脏阶段负荷。从第8天开始，通过IVIS观察到向血液期感染的过渡，然后血液期寄生虫血症增加，其动力学类似于在受控的人疟疾感染中观察到的动力学。为了评估该模型的实用性，我们测试了靶向红细胞侵袭配体网织红细胞结合蛋白同系物5（具有已知的体外生长抑制活性）的单克隆抗体是否能够在寄生虫从肝脏出现时阻断体内血液阶段感染，并发现其非常有效。总之，这些结果表明，用表达谷胱甘肽转移酶的恶性疟原虫感染的组合的肝脏人源化和血液人源化FRGN小鼠模型将是研究恶性疟原虫红细胞前期和红细胞期的有用工具，并且能够测试靶向寄生虫感染的一个或两个阶段的干预措施。
The invention of liver-humanized mouse models has made it possible to directly study the preerythrocytic stages of Plasmodium falciparum. In contrast, the current models to directly study blood stage infection in vivo are extremely limited. Humanization of the mouse blood stream is achievable by frequent injections of human red blood cells (hRBCs) and is currently the only system with which to study human malaria blood stage infections in a small animal model. Infections have been primarily achieved by direct injection of P. falciparum-infected RBCs but as such, this modality of infection does not model the natural route of infection by mosquito bite and lacks the transition of parasites from liver stage infection to blood stage infection. Including these life cycle transition points in a small animal model is of relevance for testing therapeutic interventions. To this end, we used FRGN KO mice that were engrafted with human hepatocytes and performed a blood exchange under immune modulation to engraft the animals with more than 50% hRBCs. These mice were infected by mosquito bite with sporozoite stages of a luciferase-expressing P. falciparum parasite, resulting in noninvasively measurable liver stage burden by in vivo bioluminescent imaging (IVIS) at days 5-7 postinfection. Transition to blood stage infection was observed by IVIS from day 8 onward and then blood stage parasitemia increased with a kinetic similar to that observed in controlled human malaria infection. To assess the utility of this model, we tested whether a monoclonal antibody targeting the erythrocyte invasion ligand reticulocyte-binding protein homolog 5 (with known growth inhibitory activity in vitro) was capable of blocking blood stage infection in vivo when parasites emerge from the liver and found it highly effective. Together, these results show that a combined liver-humanized and blood-humanized FRGN mouse model infected with luciferase-expressing P. falciparum will be a useful tool to study P. falciparum preerythrocytic and erythrocytic stages and enables the testing of interventions that target either one or both stages of parasite infection.