Leishmaniasis, a major globally re-emerging neglected tropical disease, has a restricted repertoire of chemotherapeutic options due to a narrow therapeutic index, drug resistance, or patient non-compliance due to toxicity. The disease is caused by the parasite that resides in two different forms in two different environments: as sessile intracellular amastigotes within mammalian macrophages and as motile promastigotes in sandfly gut. As mitogen-activated protein kinases (MAPKs) play important roles in cellular differentiation and survival, we studied the expression of MAPKs (LdMAPKs). The homology studies by multiple sequence alignment show that excepting LdMAPK1 and LdMAPK2, all thirteen other LdMAPKs share homology with human ERK and p38 isoforms. Expression of LdMAPK4 and LdMAPK5 is less in avirulent promastigotes and amastigotes. Compared to miltefosine-sensitive parasites, miltefosine-resistant parasites have higher LdMAPK1, LdMAPK3-5, LdMAPK7-11, LdMAPK13, and LdMAPK14 expression. IL-4-treatment of macrophages down-regulated LdMAPK11, in virulent amastigotes whereas up-regulated LdMAPK5, but down-regulated LdMAPK6, LdMAPK12-15, expression in avirulent amastigotes. IL-4 up-regulated LdMAPK1 expression in both virulent and avirulent amastigotes. IFN-γ-treatment down-regulated LdMAPK6, LdMAPK13, and LdMAPK15 in avirulent amastigotes but up-regulated in virulent amastigotes. This complex profile of LdMAPKs expression among virulent and avirulent parasites, drug-resistant parasites, and in amastigotes within IL-4 or IFN-γ-treated macrophages suggests that LdMAPKs are differentially controlled at the host-parasite interface regulating parasite survival and differentiation, and in the course of IL-4 or IFN-γ dominated immune response.

中文翻译：

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杜氏利什曼原虫丝裂原激活蛋白激酶作为宿主-寄生虫相互作用界面


利什曼病是全球重新出现的一种被忽视的主要热带疾病，由于治疗指数狭窄、耐药性或患者因毒性而不依从治疗，其化疗选择有限。该疾病是由存在于两种不同环境中的两种不同形式的寄生虫引起的：作为哺乳动物巨噬细胞内的无柄细胞内无鞭毛体和作为白蛉肠道内的活动前鞭毛体。由于丝裂原激活蛋白激酶 (MAPK) 在细胞分化和存活中发挥重要作用，我们研究了 MAPK (LdMAPK) 的表达。多重序列比对同源性研究表明，除LdMAPK1和LdMAPK2外，其他13个LdMAPK均与人ERK和p38亚型具有同源性。 LdMAPK4 和 LdMAPK5 在无毒力的前鞭毛体和无鞭毛体中表达较少。与米替福辛敏感寄生虫相比，米替福辛耐药寄生虫具有更高的 LdMAPK1、LdMAPK3-5、LdMAPK7-11、LdMAPK13 和 LdMAPK14 表达。巨噬细胞的 IL-4 处理下调了有毒无鞭毛体中 LdMAPK11 的表达，而上调了无毒无鞭毛体中 LdMAPK5 的表达，但下调了 LdMAPK6、LdMAPK12-15 的表达。 IL-4 上调有毒和无毒无鞭毛体中 LdMAPK1 的表达。 IFN-γ治疗下调无毒无鞭毛体中的 LdMAPK6、LdMAPK13 和 LdMAPK15，但在有毒无鞭毛体中上调。 LdMAPK 在有毒和无毒寄生虫、耐药寄生虫以及 IL-4 或 IFN-γ 处理的巨噬细胞内的无鞭毛体中表达的复杂谱表明，LdMAPK 在调节寄生虫生存和分化的宿主-寄生虫界面受到差异性控制，并且在IL-4或IFN-γ主导的免疫反应过程中。