The Trypanosoma cruzi Protease Cruzain Mediates Immune Evasion
The Trypanosoma cruzi Protease Cruzain Mediates Immune Evasion
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DOI：
10.1371/journal.ppat.1002139
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发表时间：
2011-09-01
期刊：
影响因子：
6.7
通讯作者：
Engel, Juan C.
中科院分区：
文献类型：
--
作者：
Doyle, Patricia S.;Zhou, Yuan M.;Engel, Juan C.
克氏锥虫是南美锥虫病的病原体。用药物K11777的新型化疗靶向主要的半胱氨酸蛋白酶cruzain并破坏无鞭毛体细胞内发育。然而，由于基因冗余，cruzain基因敲除失败，蛋白酶在感染和发病机制中的生物学作用仍不清楚。T的角色。在亲本野生型和Cruzain缺陷型寄生虫的比较研究中阐明了免疫逃避中的Cruzi半胱氨酸蛋白酶Cruzain。野生型T. Cruzi在感染早期（< 60分钟）没有激活宿主巨噬细胞，并且没有检测到类似于P1 κ B的增加。信号传导因子NF-κ B P65与cruzain共定位在细胞内野生型寄生虫的细胞表面上，并被蛋白水解切割。感染野生型T细胞的巨噬细胞中IL-12表达不明显。cruzi并用LPS和BFA处理，证实巨噬细胞活化途径受损。与此相反，cruzain缺陷型寄生虫诱导巨噬细胞活化，可检测的i κ B磷酸化，和核NF-κ B P65定位。这些寄生虫不能在细胞内发育并在巨噬细胞内存活。Cruzain缺陷型T. cruzi与LPS激活的对照相当。因此，cruzain通过中断NF-κ B P65介导的信号传导途径，在感染的早期（< 60分钟）阶段阻碍巨噬细胞活化。这些早期事件让T. cruzi存活和复制，并可能导致急性恰加斯病感染的传播。
Trypanosoma cruzi is the causative agent of Chagas' disease. Novel chemotherapy with the drug K11777 targets the major cysteine protease cruzain and disrupts amastigote intracellular development. Nevertheless, the biological role of the protease in infection and pathogenesis remains unclear as cruzain gene knockout failed due to genetic redundancy. A role for the T. cruzi cysteine protease cruzain in immune evasion was elucidated in a comparative study of parental wild type- and cruzain-deficient parasites. Wild type T. cruzi did not activate host macrophages during early infection (< 60 min) and no increase in similar to P i kappa B was detected. The signaling factor NF-kappa B P65 colocalized with cruzain on the cell surface of intracellular wild type parasites, and was proteolytically cleaved. No significant IL-12 expression occurred in macrophages infected with wild type T. cruzi and treated with LPS and BFA, confirming impairment of macrophage activation pathways. In contrast, cruzain-deficient parasites induced macrophage activation, detectable i kappa B phosphorylation, and nuclear NF-kappa B P65 localization. These parasites were unable to develop intracellularly and survive within macrophages. IL 12 expression levels in macrophages infected with cruzain-deficient T. cruzi were comparable to LPS activated controls. Thus cruzain hinders macrophage activation during the early (< 60 min) stages of infection, by interruption of the NF-kappa B P65 mediated signaling pathway. These early events allow T. cruzi survival and replication, and may lead to the spread of infection in acute Chagas' disease.