P53-mediated rapid induction of apoptosis conveys resistance to viral infection in Drosophila melanogaster.
P53-mediated rapid induction of apoptosis conveys resistance to viral infection in Drosophila melanogaster.
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DOI：
10.1371/journal.ppat.1003137
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发表时间：
2013-02
期刊：
影响因子：
6.7
通讯作者：
Zhou L
中科院分区：
文献类型：
--
作者：
Liu B;Behura SK;Clem RJ;Schneemann A;Becnel J;Severson DW;Zhou L
节肢动物传播的病原体每年造成数百万人死亡。了解控制病媒对病原体易感性的遗传机制，对于开发控制虫媒传染病的新策略具有深远意义。许多病毒携带具有抗凋亡活性的基因这一事实长期以来导致了这样的假设，即诱导凋亡可能是一种基本的先天免疫应答。然而，介导病毒感染后诱导细胞凋亡的细胞机制仍然是谜，这阻碍了细胞凋亡在限制病毒感染昆虫中的功能意义的实验验证。此外，对培养的昆虫细胞的研究表明，有时缺乏凋亡，或者促凋亡反应发生相对较晚，从而对凋亡作为先天免疫的功能意义产生怀疑。使用体内蚊子模型和天然感染途径，我们发现在暴露于DNA或RNA病毒后的几个小时内，有一个快速诱导收割者样促凋亡基因。在果蝇中重述类似的反应，我们发现这种快速诱导凋亡需要P53的功能，并通过reaper上游的应激反应调节区介导。更重要的是，我们发现细胞凋亡的快速诱导是阻止病毒基因表达和阻断感染的原因。影响这种快速诱导收割者样促凋亡基因的遗传变化导致对病毒感染的易感性的显着差异。节肢动物传播的病原体每年造成数百万人死亡。了解控制节肢动物对病原体易感性的遗传机制对开发控制昆虫传播的传染病的新策略具有深远的意义。虽然它被假定为细胞凋亡（一种遗传控制的细胞自杀形式）可能在昆虫先天免疫中对病毒感染发挥非常重要的作用，由于缺乏对病毒感染后诱导细胞凋亡的调控途径的知识，直接证据一直缺乏。在这项研究中，我们发现，有一个快速诱导促凋亡基因在1-3小时内暴露于病毒。这种快速的促凋亡反应仅在活体动物中观察到，但在培养的细胞中未观察到。遗传分析表明，缺乏这种快速促凋亡反应的动物对病毒感染过敏。因此，我们的工作提供了明确的证据表明，快速诱导细胞凋亡在介导昆虫对病毒感染的抗性中起着非常重要的作用。
Arthropod-borne pathogens account for millions of deaths each year. Understanding the genetic mechanisms controlling vector susceptibility to pathogens has profound implications for developing novel strategies for controlling insect-transmitted infectious diseases. The fact that many viruses carry genes that have anti-apoptotic activity has long led to the hypothesis that induction of apoptosis could be a fundamental innate immune response. However, the cellular mechanisms mediating the induction of apoptosis following viral infection remained enigmatic, which has prevented experimental verification of the functional significance of apoptosis in limiting viral infection in insects. In addition, studies with cultured insect cells have shown that there is sometimes a lack of apoptosis, or the pro-apoptotic response happens relatively late, thus casting doubt on the functional significance of apoptosis as an innate immunity. Using in vivo mosquito models and the native route of infection, we found that there is a rapid induction of reaper-like pro-apoptotic genes within a few hours following exposure to DNA or RNA viruses. Recapitulating a similar response in Drosophila, we found that this rapid induction of apoptosis requires the function of P53 and is mediated by a stress–responsive regulatory region upstream of reaper. More importantly, we showed that the rapid induction of apoptosis is responsible for preventing the expression of viral genes and blocking the infection. Genetic changes influencing this rapid induction of reaper-like pro-apoptotic genes led to significant differences in susceptibility to viral infection. Arthropod-borne pathogens account for millions of deaths each year. Understanding the genetic mechanisms controlling arthropod susceptibility to pathogens has profound implications for developing novel strategies for controlling insect-transmitted infectious diseases. Although it was postulated that apoptosis (a genetically controlled form of cellular suicide) may play a very important role in insect innate immunity against viral infection, direct evidence has been lacking due to the lack of knowledge on the regulatory pathways responsible for the induction of apoptosis following viral infection. In this study, we found that there is a rapid induction of pro-apoptotic genes within 1–3 hours of exposure to virus. This rapid pro-apoptotic response was only observed in live animals but not in cultured cells. Genetic analysis indicated that animals lacking this rapid pro-apoptotic response were hypersensitive to viral infection. Thus our work provides unequivocal evidence indicating that rapid induction of apoptosis plays a very important role in mediating insect resistance to viral infection.
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DOI：
10.4049/jimmunol.1101459
发表时间：
2011-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Muñoz-Fontela C;Pazos M;Delgado I;Murk W;Mungamuri SK;Lee SW;García-Sastre A;Moran TM;Aaronson SA
通讯作者：
Aaronson SA
影响因子：
5.3
作者：
Lin, Nianwei;Li, Xingguo;Zhou, Lei
通讯作者：
Zhou, Lei
影响因子：
12.4
作者：
Liu, B.;Becnel, J. J.;Zhou, L.
通讯作者：
Zhou, L.
影响因子：
11.8
作者：
Fan, Yun;Bergmann, Andreas
通讯作者：
Bergmann, Andreas
影响因子：
3
作者：
Lanman, Jason;Crum, John;Johnson, John E.
通讯作者：
Johnson, John E.