Innate Immunity Induced by Plasmodium Liver Infection Inhibits Malaria Reinfections
Innate Immunity Induced by Plasmodium Liver Infection Inhibits Malaria Reinfections
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DOI：
10.1128/iai.02796-14
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发表时间：
2015-03-01
影响因子：
3.1
通讯作者：
Prudencio, Miguel
中科院分区：
文献类型：
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作者：
Liehl, Peter;Meireles, Patrcia;Prudencio, Miguel
在通过蚊子叮咬传播到哺乳动物宿主后，疟原虫首先入侵并在肝细胞内复制，然后感染红细胞并导致疟疾。在疟疾流行地区，人们主要通过研究感染的血液阶段诱导的抵抗力来探索限制疟原虫再感染的机制。然而，流行病学研究表明，在高传播地区，红细胞前期也会激活宿主对再次感染的抵抗力。这一点，加上最近发现肝脏感染触发了特异性和有效的I型干扰素(干扰素)反应，促使我们假设这种红细胞期前诱导的抵抗与肝脏的先天免疫有关。在这里，我们结合实验方法和数学模型来总结实地研究，并了解这种抗性背后的分子基础。我们提出了一个新建立的小鼠再感染模型，并证明了啮齿动物疟疾肝脏阶段感染抑制了再感染。这种保护依赖于天然免疫的激活，涉及I型干扰素反应和抗微生物细胞因子γ干扰素(干扰素-γ)。重要的是，数学模拟表明，基于我们的实验性小鼠再感染模型的预测符合现有的流行病学数据。总体而言，我们的研究表明，肝脏阶段诱导的先天免疫可能有助于在疟疾高流行地区观察到的人类红细胞前抵抗。
Following transmission through a mosquito bite to the mammalian host, Plasmodium parasites first invade and replicate inside hepatocytes before infecting erythrocytes and causing malaria. The mechanisms limiting Plasmodium reinfections in humans living in regions of malaria endemicity have mainly been explored by studying the resistance induced by the blood stage of infection. However, epidemiologic studies have suggested that in high-transmission areas, preerythrocytic stages also activate host resistance to reinfection. This, along with the recent discovery that liver infections trigger a specific and effective type I interferon (IFN) response, prompted us to hypothesize that this pre-erythrocyte-stage-induced resistance is linked to liver innate immunity. Here, we combined experimental approaches and mathematical modeling to recapitulate field studies and understand the molecular basis behind such resistance. We present a newly established mouse reinfection model and demonstrate that rodent malaria liver-stage infection inhibits reinfection. This protection relies on the activation of innate immunity and involves the type I IFN response and the antimicrobial cytokine gamma IFN (IFN-gamma). Importantly, mathematical simulations indicate that the predictions based on our experimental murine reinfection model fit available epidemiological data. Overall, our study revealed that liver-stage-induced innate immunity may contribute to the preerythrocytic resistance observed in humans in regions of malaria hyperendemicity.