Genetically attenuated Plasmodium berghei liver stages induce sterile protracted protection that is mediated by major histocompatibility complex class I-dependent interferon-γ-producing CD8+ T cells
Genetically attenuated Plasmodium berghei liver stages induce sterile protracted protection that is mediated by major histocompatibility complex class I-dependent interferon-γ-producing CD8+ T cells
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DOI：
10.1086/519743
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发表时间：
2007-08-15
影响因子：
6.4
通讯作者：
Krzych, Urszula
中科院分区：
文献类型：
--
作者：
Jobe, Ousman;Lumsden, Joanne;Krzych, Urszula
目前，辐射减毒疟原虫子孢子(Gamma-SPZ)是唯一一种对未感染疟疾的人和实验室啮齿动物具有无菌和持久保护作用的疫苗。然而，伽马-SPZ也不是没有风险。例如，伽马-SPZ的异质性可以解释偶尔的突破性感染。为了避免这种可能性，我们通过移除在感染性SPZ中上调表达的两个基因UIS3和UIS4构建了一个双敲除伯氏疟原虫寄生虫。我们评估了双敲除Pbuis3(-)/4(-)寄生虫的保护效果和CD8(+)T细胞对保护的贡献。Pbuis3(-)/4(-)SPZ对C57BL/6小鼠具有不育和持久保护作用。鉴于缺乏β(2)m的小鼠没有受到保护，保护与CD8(+)T细胞有关。Pbuis3(-)/4(-)SPZ免疫CD8(+)T细胞由效应/记忆表型组成，并产生干扰素-γ。在这些观察的基础上，我们建议发展基因减毒的恶性疟原虫作为红细胞前期候选疫苗在临床试验中是有必要的。
At present, radiation-attenuated plasmodia sporozoites (gamma-spz) is the only vaccine that induces sterile and lasting protection in malaria-naive humans and laboratory rodents. However, gamma-spz are not without risks. For example, the heterogeneity of the gamma-spz could explain occasional breakthrough infections. To avoid this possibility, we constructed a double-knockout P. berghei parasite by removing 2 genes, UIS3 and UIS4, that are up-regulated in infective spz. We evaluated the double-knockout Pbuis3(-)/4(-) parasites for protective efficacy and the contribution of CD8(+) T cells to protection. Pbuis3(-)/4(-) spz induced sterile and protracted protection in C57BL/6 mice. Protection was linked to CD8(+) T cells, given that mice deficient in beta(2)m were not protected. Pbuis3(-)/4(-) spz-immune CD8(+) T cells consisted of effector/memory phenotypes and produced interferon-gamma. On the basis of these observations, we propose that the development of genetically attenuated P. falciparum parasites is warranted for tests in clinical trials as a pre-erythrocytic stage vaccine candidate.