Caspar controls resistance to Plasmodium falciparum in diverse anopheline species.
Caspar controls resistance to Plasmodium falciparum in diverse anopheline species.
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DOI：
10.1371/journal.ppat.1000335
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发表时间：
2009-03
期刊：
影响因子：
6.7
通讯作者：
Dimopoulos G
中科院分区：
文献类型：
--
作者：
Garver LS;Dong Y;Dimopoulos G
疟疾载体冈比亚按蚊发起的免疫反应主要通过 NF-kappaB 转录因子 Rel1 和 Rel2 受 Toll 和 Imd（免疫缺陷）途径调节，而 Rel1 和 Rel2 分别由负调节因子 Cactus 和 Caspar 控制。冈比亚疟原虫中的 Rel1 和 Rel2 依赖性转录已被证明对于蚊子控制啮齿动物疟疾寄生虫伯氏疟原虫感染的能力特别重要。使用 RNA 干扰来消除这些途径的负调节因子，我们发现 Rel2 控制冈比亚疟原虫对人类疟疾寄生虫恶性疟原虫的抗性，而 Rel 1 激活可降低感染水平。通过证明 Caspar 沉默还可以防止亚洲和南美洲的主要疟疾载体（分别为 A. stephensi 和 A. albimanus）中恶性疟原虫的发展，确立了这种防御系统在按蚊物种中的普遍相关性。平行研究表明，虽然 Imd 途径激活对恶性疟原虫最有效，但 Toll 途径对伯氏疟原虫最有效，这凸显了人类病原体与其啮齿动物模型之间的显着差异。高通量基因表达分析鉴定出大量受两个 Rel 因子激活调节的基因，并揭示 Toll 途径在蚊子生物学中比 Imd 途径发挥更多样化的作用，而 Imd 途径更具免疫特异性。对关键抗疟原虫因子的进一步分析表明，它们可能与 Imd 途径介导的耐药表型有关。此外，我们发现，在糖喂养、血喂养和恶性疟原虫感染的雌性冈比亚疟原虫中，通过 Caspar 基因沉默激活 Rel2 所造成的适应度成本是检测不到的，而 Toll 途径的 Rel1 激活则产生了重大影响。这项研究首次描述了影响免疫机制的单个基因，该机制能够阻止按蚊物种中恶性疟原虫的发育。此外，这项研究还探讨了观察到的表型的分子、进化和生理后果的各个方面。这些发现对疟疾控制具有重要意义，因为不同按蚊物种的广谱免疫激活为在全球范围内开发新型疟疾控制方法提供了可行的战略方法。疟疾寄生虫与将其传播给人类的蚊子之间的关系包括复杂的分子相互作用，包括蚊子的免疫反应。按蚊可以产生有效的抗疟原虫免疫反应；我们在此表明，编码免疫信号通路 Imd 负调节因子的基因 caspar 控制着蚊子对人类疟疾寄生虫的抵抗力。沉默该 Imd 途径调节剂会导致三种不同的按蚊疟疾媒介物种对人类疟原虫产生完全抗性，但不会对啮齿类疟原虫物种产生完全抗性，表明蚊子而非多种寄生虫物种中防御功能得到保留。我们还鉴定了一组通过 caspar 基因沉默进行转录调控的基因。其中一些基因直接有助于寄生虫抵抗力。最后，我们表明，短暂的免疫激活使蚊子对人类疟疾寄生虫产生抵抗力，这对蚊子的适应性几乎没有影响，而作为实验室条件下生存或繁殖力的衡量标准。总之，这项研究表明，蚊子的免疫途径 Imd 可以通过涉及几种已知抗疟原虫基因的免疫反应来调节对疟原虫的抵抗力。
Immune responses mounted by the malaria vector Anopheles gambiae are largely regulated by the Toll and Imd (immune deficiency) pathways via the NF-kappaB transcription factors Rel1 and Rel2, which are controlled by the negative regulators Cactus and Caspar, respectively. Rel1- and Rel2-dependent transcription in A. gambiae has been shown to be particularly critical to the mosquito's ability to manage infection with the rodent malaria parasite Plasmodium berghei. Using RNA interference to deplete the negative regulators of these pathways, we found that Rel2 controls resistance of A. gambiae to the human malaria parasite Plasmodium falciparum, whereas Rel 1 activation reduced infection levels. The universal relevance of this defense system across Anopheles species was established by showing that caspar silencing also prevents the development of P. falciparum in the major malaria vectors of Asia and South America, A. stephensi and A. albimanus, respectively. Parallel studies suggest that while Imd pathway activation is most effective against P. falciparum, the Toll pathway is most efficient against P. berghei, highlighting a significant discrepancy between the human pathogen and its rodent model. High throughput gene expression analyses identified a plethora of genes regulated by the activation of the two Rel factors and revealed that the Toll pathway played a more diverse role in mosquito biology than the Imd pathway, which was more immunity-specific. Further analyses of key anti-Plasmodium factors suggest they may be responsible for the Imd pathway–mediated resistance phenotype. Additionally, we found that the fitness cost caused by Rel2 activation through caspar gene silencing was undetectable in sugar-fed, blood-fed, and P. falciparum-infected female A. gambiae, while activation of the Toll pathway's Rel1 had a major impact. This study describes for the first time a single gene that influences an immune mechanism that is able to abort development of P. falciparum in Anopheline species. Further, this study addresses aspects of the molecular, evolutionary, and physiological consequences of the observed phenotype. These findings have implications for malaria control since broad-spectrum immune activation in diverse anopheline species offers a viable and strategic approach to develop novel malaria control methods worldwide. The relationship between malaria parasites and the mosquitoes that transmit them to humans comprises complex molecular interactions including mosquito immune responses. Anopheles can mount potent anti-Plasmodium immune responses; we show here that the gene caspar, which encodes a negative regulator of the immune signaling pathway Imd, controls mosquito resistance to the human malaria parasite. Silencing of this Imd pathway regulator results in complete resistance to human Plasmodium in three divergent Anopheline malaria vector species, yet does not cause complete resistance to a rodent Plasmodium species, indicating conservation of defense function among mosquito but not diverse parasite species. We also identify a panel of genes that are transcriptionally regulated by silencing of the caspar gene. Some of these genes contribute directly to parasite resistance. Finally, we show that the transient immune activation that renders mosquitoes resistant to the human malaria parasite has little to no effect on mosquito fitness as a measure of survival or fecundity under laboratory conditions. In sum, this study shows that the mosquito's immune pathway, Imd, can regulate resistance to Plasmodium through immune responses that entail several known anti-Plasmodium genes.
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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：
Frolet, Cecile;Thoma, Martine;Levashina, Elena A.
通讯作者：
Levashina, Elena A.
DOI：
10.1073/pnas.0402180101
发表时间：
2004-07-06
影响因子：
11.1
作者：
Matsushita, M;Matsushita, A;Fujita, T
通讯作者：
Fujita, T
影响因子：
56.9
作者：
Christophides, GK;Zdobnov, E;Kafatos, FC
通讯作者：
Kafatos, FC
DOI：
10.1073/pnas.0504950102
发表时间：
2005-08-09
影响因子：
11.1
作者：
Meister, S;Kanzok, SM;Zheng, LB
通讯作者：
Zheng, LB