Fine pathogen discrimination within the APL1 gene family protects Anopheles gambiae against human and rodent malaria species.
Fine pathogen discrimination within the APL1 gene family protects Anopheles gambiae against human and rodent malaria species.
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DOI：
10.1371/journal.ppat.1000576
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发表时间：
2009-09
期刊：
影响因子：
6.7
通讯作者：
Bourgouin C
中科院分区：
文献类型：
--
作者：
Mitri C;Jacques JC;Thiery I;Riehle MM;Xu J;Bischoff E;Morlais I;Nsango SE;Vernick KD;Bourgouin C
冈比亚按蚊对恶性疟原虫的基因控制抗性是自然种群中的一个共同特征，一组自然抗性位点被映射到冈比亚按蚊基因组的疟原虫抗性岛（PRI）。 PRI 候选基因研究强调了富含亮氨酸重复 (LRR) 蛋白的 APL1 家族，该家族由具有≥50% 氨基酸同一性的旁系同源物 APL1A、APL1B 和 APL1C 组成。在这里，我们对 APL1 家族成员在蚊子感染人类和啮齿类疟原虫物种期间的联合反应进行了功能分析。只有旁系同源物 APL1A 可以保护冈比亚疟原虫免受来自野外种群和体外培养的人类疟原虫恶性疟原虫的感染。相比之下，只有旁系同源物 APL1C 能够抵抗啮齿动物疟疾寄生虫伯氏疟原虫和约氏疟原虫。我们证明了反P。恶性疟原虫的保护是由 Imd/Rel2 通路介导的，而针对伯氏疟原虫感染的保护则需要 Toll/Rel1 信号传导。此外，只有Rel2的短Rel2-S亚型而非长Rel2-F亚型能够提供针对恶性疟原虫的保护。保护作用与 Rel2-S 对 APL1A 的转录调节相关，但与 Rel2-F 无关，表明 Rel2-S 抗寄生虫表型至少部分来自其对 APL1A 的转录控制。这些结果表明 APL1 基因家族的不同成员对不同类别的疟原虫寄生虫表现出相互排斥的保护作用。看来病原体类别的基因系统针对不同类别的相似病原体确定了适当的宿主防御。众所周知，昆虫先天免疫途径可以区分完全不同的微生物，例如革兰氏阳性细菌、革兰氏阴性细菌或真菌，但 APL1 旁系同源物的功能表明，蚊子先天免疫具有比以前认识到的更细粒度的能力来区分密切相关的真核病原体类别。非洲疟疾媒介蚊子冈比亚按蚊拥有免疫机制，可以保护其免受疟原虫感染，疟原虫每年导致超过一百万人死亡。研究蚊子对疟疾反应的许多工作都使用了模型啮齿动物疟疾寄生虫，这些寄生虫不会感染人类，但与人类寄生虫属于同一属，并且总体上具有大多数主要特征。在这里，我们表明冈比亚疟原虫用于保护自身免受人类和啮齿动物疟疾寄生虫感染的免疫反应利用了不同的免疫信号通路。一个名为 APL1 的蛋白质家族似乎负责蚊子区分人类或啮齿动物疟疾寄生虫的能力。需要一个单独的 APL1 亲属才能预防人类疟疾寄生虫，但对啮齿动物寄生虫没有作用，而另一个 APL1 亲属则需要预防啮齿动物而非人类疟疾。这代表了蚊子免疫区分相对相似的病原体的最佳能力，并突显了与啮齿动物疟疾寄生虫相比，蚊子对人类反应的独特性质。
Genetically controlled resistance of Anopheles gambiae mosquitoes to Plasmodium falciparum is a common trait in the natural population, and a cluster of natural resistance loci were mapped to the Plasmodium-Resistance Island (PRI) of the A. gambiae genome. The APL1 family of leucine-rich repeat (LRR) proteins was highlighted by candidate gene studies in the PRI, and is comprised of paralogs APL1A, APL1B and APL1C that share ≥50% amino acid identity. Here, we present a functional analysis of the joint response of APL1 family members during mosquito infection with human and rodent Plasmodium species. Only paralog APL1A protected A. gambiae against infection with the human malaria parasite P. falciparum from both the field population and in vitro culture. In contrast, only paralog APL1C protected against the rodent malaria parasites P. berghei and P. yoelii. We show that anti-P. falciparum protection is mediated by the Imd/Rel2 pathway, while protection against P. berghei infection was shown to require Toll/Rel1 signaling. Further, only the short Rel2-S isoform and not the long Rel2-F isoform of Rel2 confers protection against P. falciparum. Protection correlates with the transcriptional regulation of APL1A by Rel2-S but not Rel2-F, suggesting that the Rel2-S anti-parasite phenotype results at least in part from its transcriptional control over APL1A. These results indicate that distinct members of the APL1 gene family display a mutually exclusive protective effect against different classes of Plasmodium parasites. It appears that a gene-for-pathogen-class system orients the appropriate host defenses against distinct categories of similar pathogens. It is known that insect innate immune pathways can distinguish between grossly different microbes such as Gram-positive bacteria, Gram-negative bacteria, or fungi, but the function of the APL1 paralogs reveals that mosquito innate immunity possesses a more fine-grained capacity to distinguish between classes of closely related eukaryotic pathogens than has been previously recognized. The African malaria vector mosquito Anopheles gambiae possesses immune mechanisms that can protect it against infection with malaria parasites, which kill more than one million people per year. Much work studying mosquito response to malaria has used model rodent malaria parasites that do not infect people, but are in the same genus and overall share most major features with the human parasites. Here, we show that the immune response used by A. gambiae to protect itself against infection by human and rodent malaria parasites utilizes different immune signaling pathways. A family of proteins called APL1 appears to be responsible for the ability of the mosquito to distinguish between the human or rodent malaria parasites. An individual APL1 relative is required for protection against the human malaria parasite but has no effect against the rodent parasite, and another APL1 relative is required for protection against rodent but not human malaria. This represents the finest ability yet demonstrated of mosquito immunity to distinguish between relatively similar pathogens, and highlights the distinct nature of mosquito response against human as compared to rodent malaria parasites.
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影响因子：
6.7
作者：
Dong Y;Aguilar R;Xi Z;Warr E;Mongin E;Dimopoulos G
通讯作者：
Dimopoulos G
影响因子：
32.4
作者：
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4
作者：
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通讯作者：
Deitsch, Kirk W.
影响因子：
56.9
作者：
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Kafatos, FC