Cell invasion by the protozoan parasite Trypanosoma cruzi involves activation of host signaling pathways and the recruitment and fusion of lysosomes at the parasite entry site. A major signaling pathway regulating invasion of fibroblasts, epithelial cells, and myoblasts involves mobilization of Ca(2+) from intracellular stores and requires the activity of a T. cruzi serine peptidase, oligopeptidase B (OPB). Deletion of the OPB gene results in a marked defect in trypomastigote virulence, consistent with a greatly reduced cell invasion capacity. Here we show that uptake by macrophages, on the other hand, is largely independent of OPB expression and sensitive to inhibition of by cytochalasin D. The residual invasion capacity of OPBnull trypomastigotes in fibroblasts still involves lysosome recruitment, although in a significantly delayed fashion. Transient elevations in intracellular Ca(2+) concentrations were observed in host cells exposed to both wild-type and OPBnull trypomastigotes, but the signals triggered by the mutant parasites were less vigorous and delayed. The capacity of triggering elevation in host cell cyclic AMP (cAMP), however, was unaltered in OPBnull trypomastigotes. Modulation in cAMP levels preferentially affected the residual cell invasion capacity of OPBnull parasites, suggesting that this signaling pathway can play a dominant role in promoting cell invasion in the absence of the major OPB-dependent pathway.

译文

原生动物寄生虫克氏锥虫的细胞入侵涉及宿主信号通路的激活以及溶酶体在寄生虫进入部位的募集和融合。调节成纤维细胞,上皮细胞和成肌细胞侵袭的主要信号通路涉及从细胞内存储中动员Ca(2),并且需要T. cruzi丝氨酸肽酶,寡肽酶B (OPB) 的活性。OPB基因的缺失导致锥虫毒力明显缺陷,与细胞侵袭能力大大降低一致。另一方面,在这里,我们表明巨噬细胞的摄取在很大程度上独立于OPB表达,并且对细胞松弛素D的抑制敏感。尽管成纤维细胞中OPBnull类锥虫的残余侵袭能力仍涉及溶酶体募集,尽管其延迟方式明显。在暴露于野生型和OPBnull锥虫的宿主细胞中观察到细胞内Ca(2) 浓度的瞬时升高,但是由突变寄生虫触发的信号不那么活跃和延迟。然而,在OPBnull锥虫中触发宿主细胞循环AMP (cAMP) 升高的能力并未改变。cAMP水平的调节优先影响了OPBnull寄生虫的残余细胞入侵能力,这表明在缺乏主要的OPB依赖性途径的情况下,该信号通路可以在促进细胞入侵中发挥主导作用。

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