Phosphoinositide-3-OH-kinase inhibitor LY294002 prevents activation of Ancylostoma caninum and Ancylostoma ceylanicum third-stage infective larvae
Phosphoinositide-3-OH-kinase inhibitor LY294002 prevents activation of Ancylostoma caninum and Ancylostoma ceylanicum third-stage infective larvae
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DOI：
10.1016/j.ijpara.2004.04.003
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发表时间：
2004-07-01
影响因子：
4
通讯作者：
Hawdon, JM
中科院分区：
文献类型：
--
作者：
Brand, A;Hawdon, JM
发育停滞的钩虫有效幼虫只有在入侵过程中遇到特定的宿主介导的线索后才能恢复发育。这些线索激活信号通路，最终恢复发育。在犬钩虫中，激活的特征是恢复进食和释放感染所需的排泄/分泌产物。自由生活的线虫秀丽隐杆线虫的多尔阶段是类似于钩虫感染性幼虫的发育停滞阶段。道尔幼虫响应表明有利于繁殖和生长条件的环境线索而退出发育停滞。由于 dauer 恢复和激活之间的相似性，dauer 的退出提供了钩虫幼虫激活的模型。胰岛素信号通路与控制线虫和犬线虫幼虫的发育停滞退出有关。为了进一步研究胰岛素信号在钩虫幼虫激活中的作用，使用恢复摄食作为激活标记，测试了磷脂酰肌醇-3-OH激酶抑制剂LY294002对体外激活的影响。 LY294002 阻止用宿主血清滤液和谷胱甘肽类似物、毒蕈碱激动剂槟榔碱或细胞渗透性 cGMP 类似物 8-溴-cGMP 刺激的犬曲霉感染性幼虫的摄食。在同属钩虫锡兰钩虫中也观察到了类似的结果。这些数据表明，钩虫幼虫（如秀丽隐杆线虫）中的胰岛素信号传导途径介质被激活，并且磷脂酰肌醇-3-OH激酶抑制剂在该途径中的cGMP和毒蕈碱信号传导步骤的下游起作用。在犬曲霉中，LY294002 对与激活相关的排泄/分泌产物的释放没有影响，表明分泌途径与磷脂酰肌醇-3-OH 激酶步骤上游的激活途径不同。这些结果为胰岛素信号通路作为钩虫幼虫寄生激活的主要通路提供了额外的支持。 (C) 2004 年澳大利亚寄生虫学协会。由 Elsevier Ltd 出版。保留所有权利。
The developmentally arrested hookworm effective larva resumes development only after encountering specific host-mediated cues during invasion. These cues activate a signaling Pathway that culminates in the resumption of development. In Ancylostoma caninum, activation is characterised by the resumption of feeding and the release of excretory/secretory products required for infection. The dauer stage of the free-living nematode Caenorhabditis elegans is a developmentally arrested stage analogous to the hookworm infective larva. Dauer larvae exit developmental arrest in response to environmental cues that indicate favorable conditions for reproduction and growth. Because of the similarity between dauer recovery and activation, exit from dauer provides a model for hookworm larval activation. An insulin-signaling pathway has been implicated in controlling exit from developmental arrest in both C. elegans dauers and A. caninum larvae. To further investigate the role of insulin signaling in hookworm larval activation, the phosphatidylinositol-3-OH kinase inhibitor LY294002 was tested for its effect on in vitro activation using the resumption of feeding as a marker for activation. LY294002 prevented feeding in A. caninum infective larvae stimulated with host serum filtrate and a glutathione-analogue, the muscarinic agonist arecoline, or the cell permeable cGMP-analogue 8-bromo-cGMP. Similar results were seen with the congeneric hookworm Ancylostoma ceylanicum. These data suggest that an insulin-signaling pathway mediaf&s -activation in hookworm larvae, as in C. elegans, and that the phosphatidylinositol-3-OH kinase inhibitor acts downstream of the cGMP and muscarinic signaling steps in the pathway. In A. caninum, LY294002 had no effect on the release of excretory/secretory products associated with activation, suggesting that the secretory pathway diverges from the activation pathway upstream of the phosphatidylinositol-3-OH kinase step. These results provide additional support for the insulin-signaling pathway as the primarily pathway for activation to parasitism in hookworm larvae. (C) 2004 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.