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首页> 外文期刊>Infection and immunity >A New Cruzipain-Mediated Pathway of Human Cell Invasion by Trypanosoma cruzi Requires Trypomastigote Membranes
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A New Cruzipain-Mediated Pathway of Human Cell Invasion by Trypanosoma cruzi Requires Trypomastigote Membranes

机译：克鲁氏锥虫对人细胞的新的克鲁斯帕坦介导的途径需要Trypomastigote膜。

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The intracellular protozoan Trypanosoma cruzi causes Chagas' disease, a chronic illness associated with cardiomyopathy and digestive disorders. This pathogen invades mammalian cells by signaling them through multiple transduction pathways. We previously showed that cruzipain, the main cysteine protease of T. cruzi, promotes host cell invasion by activating kinin receptors. Here, we report a cruzipain-mediated invasion route that is not blocked by kinin receptor antagonists. By testing different strains of T. cruzi, we observed a correlation between the level of cruzipain secreted by trypomastigotes and the capacity of the pathogen to invade host cells. Consistent with a role for cruzipain, the cysteine protease inhibitor N-methylpiperazine-urea-Phe-homophenylalanine-vinylsulfone-benzene impaired the invasion of human smooth muscle cells by strains Dm28c and X10/6 but not by the G isolate. Cruzipain-rich supernatants of Dm28c trypomastigotes enhanced the infectivity of isolate G parasites twofold, an effect which was abolished by the cysteine protease inhibitor l-trans-epoxysuccinyl-leucylamido-(4-guanidino)butane and by thapsigargin, a drug that induces depletion of the intracellular Ca2+ stores. The enhancement due to Dm28 supernatants was abolished upon cruzipain immunodepletion, and the activity was restored by purified cruzipain. In contrast, supernatants from isolate G trypomastigotes (with low levels of cruzipain) or supernatants from Dm28c epimastigotes or purified cruzipain alone did not enhance parasite invasion, indicating that the protease is required but not sufficient to engage this invasion pathway. We provide evidence that activation of this pathway requires cruzipain-mediated processing of a trypomastigote molecule associated with parasite-shed membranes. Our results couple cruzipain to host cell invasion through a kinin-independent route and further suggest that high-level cruzipain expression may contribute to parasite infectivity.
机译：细胞内原生动物 Trypanosoma cruzi 引起查加斯病，这是一种与心肌病和消化系统疾病有关的慢性疾病。该病原体通过多种转导途径向哺乳动物细胞发出信号，从而侵入哺乳动物细胞。我们先前显示了Cruzipain，这是 T的主要半胱氨酸蛋白酶。 cruzi 通过激活激肽受体促进宿主细胞的侵袭。在这里，我们报道了一个激肽受体介导的入侵途径未被激肽受体拮抗剂阻断。通过测试不同的 T菌株。在Cruzi 中，我们观察到了由锥虫鞭毛虫分泌的Cruzipain的水平与病原体入侵宿主细胞的能力之间的相关性。与Cruzipain的作用一致，半胱氨酸蛋白酶抑制剂 N -甲基哌嗪-脲-Phe-高苯丙氨酸-乙烯基砜-苯损害了Dm28c和X10 / 6菌株对人平滑肌细胞的入侵，但对G隔离株。 Dm28c准鞭毛体富含Cruzipain的上清液将分离的G寄生虫的感染力提高了两倍，半胱氨酸蛋白酶抑制剂1-反式-反式-琥珀酸-亮氨酰-（4-胍基）丁烷和thapsigargin消除了这种作用。 ，一种诱导细胞内Ca 2 + 储存耗尽的药物。在Cruzipain免疫耗竭后，由于Dm28上清液引起的增强作用被消除，并且通过纯化的Cruzipain恢复了活性。相比之下，来自分离物G锥虫的上清液或少量Dm28c附睾的上清液或单独纯化的Cruzipain上清液不能增强寄生虫的入侵，表明该蛋白酶是必需的，但不足以参与这种入侵途径。我们提供的证据表明，该途径的激活需要用克鲁巴萨蛋白酶介导的与寄生虫脱落的膜相关的类鞭毛鞭毛虫分子的加工。我们的研究结果通过一个独立于激肽的途径将Cruzipain偶联到宿主细胞的侵袭中，并进一步表明高水平Cruzipain表达可能有助于寄生虫感染。

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