Anopheles Imd pathway factors and effectors in infection intensity-dependent anti-Plasmodium action.
Anopheles Imd pathway factors and effectors in infection intensity-dependent anti-Plasmodium action.
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DOI：
10.1371/journal.ppat.1002737
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发表时间：
2012
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;Bahia AC;Das S;Souza-Neto JA;Shiao J;Dong Y;Dimopoulos G
冈比亚按蚊对恶性疟原虫的免疫反应是人类疟疾的一种病原体，已被确定为潜在的抗疟原虫基因来源和可用于控制疟疾传播周期的机制。其中一种机制是IMD途径，这是一种保守的免疫信号途径，具有强大的抗P。恶性疟原虫活动。沉默IMD途径的负调控因子Caspar的表达，或过表达IMD途径控制的NFkappaB转录因子rel2，可以赋予冈比亚按蚊一种涉及一系列免疫效应基因的抗性表型。然而，这一强大机制中可能对执行疟疾控制战略至关重要的未被探索的特征仍然存在。利用RNA干扰使Caspar和IMD途径的其他组件沉默，我们已经鉴定了参与Caspar调控的抗疟原虫信号模块的基因，每个基因都代表着实现该途径过度激活的潜在靶点。我们还确定，IMD途径对寄生虫的卵动期最有效，但对早期卵囊也有一定的活性，对晚期卵囊的活性较小。我们进一步证明，仅Caspar沉默就足以诱导出强大的抗P.即使在相对缺乏肠道微生物区系的情况下，恶性疟原虫也会产生反应。最后，我们建立了寄生虫感染强度依赖防御中IMD途径组件和调节效应因子TEP1、APL1和LRIM1的相关性，从而揭示了实验室和自然感染强度模型的相关性。我们的结果突出了在冈比亚按蚊中深思熟虑地实施IMD途径操作所必需的生理学考虑，作为限制疟疾传播周期的努力的一部分，它们揭示了IMD指导的针对恶性疟原虫的免疫反应中的各种以前未知的细微差别。蚊媒疟原虫的免疫应答已被证明具有强大的抗疟原虫防御能力。作为这些免疫反应的主要调节者，信号通路，特别是似乎特别有能力消除疟疾寄生虫的IMD通路，已成为疟疾控制干预措施的有吸引力的目标。虽然IMD途径的一般抗寄生虫活性已经确定，但所涉及的途径的特定成分以及该途径能够限制感染的生理条件大多尚不清楚。了解这些主要参与者和情况对于将IMD途径转变为干预策略至关重要。我们报告说，虽然IMD途径的几个成员对这种反应是关键的，但其他成员是必不可少的。我们还表明，对感染的反应时间和感染暴露的强度都影响IMD衍生的抗疟原虫反应的有效性，而肠道菌群的状态不影响。综上所述，这些数据为基于这一途径的有效干预奠定了必要的基础，这一途径可以严重限制蚊子感染人类疟疾寄生虫。
The Anopheles gambiae immune response against Plasmodium falciparum, an etiological agent of human malaria, has been identified as a source of potential anti-Plasmodium genes and mechanisms to be exploited in efforts to control the malaria transmission cycle. One such mechanism is the Imd pathway, a conserved immune signaling pathway that has potent anti-P. falciparum activity. Silencing the expression of caspar, a negative regulator of the Imd pathway, or over-expressing rel2, an Imd pathway-controlled NFkappaB transcription factor, confers a resistant phenotype on A. gambiae mosquitoes that involves an array of immune effector genes. However, unexplored features of this powerful mechanism that may be essential for the implementation of a malaria control strategy still remain. Using RNA interference to singly or dually silence caspar and other components of the Imd pathway, we have identified genes participating in the anti-Plasmodium signaling module regulated by Caspar, each of which represents a potential target to achieve over-activation of the pathway. We also determined that the Imd pathway is most potent against the parasite's ookinete stage, yet also has reasonable activity against early oocysts and lesser activity against late oocysts. We further demonstrated that caspar silencing alone is sufficient to induce a robust anti-P. falciparum response even in the relative absence of resident gut microbiota. Finally, we established the relevance of the Imd pathway components and regulated effectors TEP1, APL1, and LRIM1 in parasite infection intensity-dependent defense, thereby shedding light on the relevance of laboratory versus natural infection intensity models. Our results highlight the physiological considerations that are integral to a thoughtful implementation of Imd pathway manipulation in A. gambiae as part of an effort to limit the malaria transmission cycle, and they reveal a variety of previously unrecognized nuances in the Imd-directed immune response against P. falciparum. The immune response of the mosquito vector of Plasmodium has proven to possess powerful anti-Plasmodium defense capabilities. As the major regulators of these immune responses, signaling pathways, particularly the Imd pathway which seems especially capable of eliminating malaria parasites, have become attractive candidates targets for malaria-control interventions. Although the general anti-parasitic activity of the Imd pathway has been established, the particular components of the pathway involved and the physiological conditions under which the pathway is capable of limiting infection are mostly unknown. Awareness of these major players and conditions is crucial for adapting the Imd pathway into an intervention strategy. We report that while several members of the Imd pathway are critical for such a response, others are dispensable. We also show that timing of the response with regard to infection and intensity of infection exposure both influence the effectiveness of an Imd-derived anti-Plasmodium response while the status of the gut flora does not. Taken together, this data lays the essential groundwork for effective intervention based on manipulation of this pathway that can severely limit mosquito infection with human malaria parasites.
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影响因子：
6.7
作者：
Mitri C;Jacques JC;Thiery I;Riehle MM;Xu J;Bischoff E;Morlais I;Nsango SE;Vernick KD;Bourgouin C
通讯作者：
Bourgouin C
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：
10.4269/ajtmh.1996.54.214
发表时间：
1996-02-01
影响因子：
3.3
作者：
Pumpuni, CB;DeMaio, J;Beier, JC
通讯作者：
Beier, JC
影响因子：
56.9
作者：
Christophides, GK;Zdobnov, E;Kafatos, FC
通讯作者：
Kafatos, FC