Genetically modified Plasmodium parasites as a protective experimental malaria vaccine
Genetically modified Plasmodium parasites as a protective experimental malaria vaccine
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DOI：
10.1038/nature03188
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发表时间：
2005-01-13
期刊：
影响因子：
64.8
通讯作者：
Matuschewski, K
中科院分区：
文献类型：
--
作者：
Mueller, AK;Labaied, M;Matuschewski, K
疟疾是一种蚊子传播的疾病，通过接种疟原虫子孢子阶段的寄生虫传播。子孢子侵入肝细胞（1），转化为肝阶段，随后的肝阶段发育最终导致致病性裂殖子的释放（2）。寄生虫的肝脏阶段是疟疾疫苗的主要目标，因为它们可以通过消除免疫反应而完全消除，从而预防疟疾感染（3）。使用表达谱，我们先前鉴定了仅在寄生虫的红细胞前阶段表达的基因（4，5）。在这里，我们通过反向遗传学表明，一个确定的基因，UIS3（在感染性子孢子基因3中上调），是肝脏早期发育所必需的。UIS3缺陷型子孢子感染肝细胞，但不能在体内建立血液期感染，因此不会导致疾病。用uis3缺陷子孢子免疫在啮齿动物疟疾模型中提供对感染性子孢子攻击的完全保护。这种保护是持续的，并针对具体阶段。我们的研究结果表明，安全有效的遗传减毒全生物体疟疾疫苗是可能的。
Malaria is a mosquito-borne disease that is transmitted by inoculation of the Plasmodium parasite sporozoite stage. Sporozoites invade hepatocytes(1), transform into liver stages, and subsequent liver-stage development ultimately results in release of pathogenic merozoites(2). Liver stages of the parasite are a prime target for malaria vaccines because they can be completely eliminated by sterilizing immune responses, thereby preventing malarial infection(3). Using expression profiling, we previously identified genes that are only expressed in the pre-erythrocytic stages of the parasite(4,5). Here, we show by reverse genetics that one identified gene, UIS3 (upregulated in infective sporozoites gene 3), is essential for early liver-stage development. uis3-deficient sporozoites infect hepatocytes but are unable to establish blood-stage infections in vivo, and thus do not lead to disease. Immunization with uis3-deficient sporozoites confers complete protection against infectious sporozoite challenge in a rodent malaria model. This protection is sustained and stage specific. Our findings demonstrate that a safe and effective, genetically attenuated whole-organism malaria vaccine is possible.