Leishmania infantum Induces Mild Unfolded Protein Response in Infected Macrophages.
Leishmania infantum Induces Mild Unfolded Protein Response in Infected Macrophages.
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DOI：
10.1371/journal.pone.0168339
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Magnani M
中科院分区：
文献类型：
--
作者：
Galluzzi L;Diotallevi A;De Santi M;Ceccarelli M;Vitale F;Brandi G;Magnani M
利什曼病是由利什曼原虫属的原生动物引起的一组寄生虫病，影响人类和其他脊椎动物。利什曼原虫是一种细胞内病原体，能够在巨噬细胞感染的早期阶段通过激活宿主PI 3 K/Akt途径和抑制caspase-3激活来赋予对凋亡的抗性。细胞内病原体劫持细胞器如ER以促进存活和复制，从而引发ER应激并激活/调节宿主细胞中的未折叠蛋白反应（UPR）。UPR旨在减轻ER应激，从而促进细胞存活。然而，长期的ER应激将激活凋亡途径。本研究的目的是研究利什曼原虫感染的巨噬细胞的内质网应激反应，以了解寄生细胞抗凋亡的机制。用婴儿利什曼原虫MHOM/TN/80/IPT 1（WHO国际参考株）感染从人单核细胞系（U937和THP-1）分化的巨噬细胞和鼠原代巨噬细胞。通过qPCR和/或蛋白质印迹法评价了几种ER应激/自噬表达标志物以及细胞存活/凋亡标志物（磷酸化Akt和裂解的半胱天冬酶-3）。作为ER应激阳性对照，用衣霉素或二硫苏糖醇（DTT）处理细胞。基因表达分析显示ER应激/自噬标记物的轻微但显著的诱导。western blot分析显示，经衣霉素和DTT处理的细胞中，利什曼原虫感染诱导Akt磷酸化，并显著抑制caspase-3切割、eIF 2 α磷酸化和DDIT 3/CHOP表达的诱导。感染细胞中ER应激表达标志物的轻微但显著的增加和ER应激诱导剂作用的延迟/减弱支持了L.婴儿可通过诱导轻微的内质网应激反应来促进宿主细胞的存活。宿主内质网应激反应不仅是利什曼原虫常见的致病机制，也是开发新药的靶点。
The Leishmaniases are a group of parasitic diseases caused by protozoa of the Leishmania genus affecting both humans and other vertebrates. Leishmania is an intracellular pathogen able to confer resistance to apoptosis in the early phase of macrophages infection by activation of host PI3K/Akt pathway and inhibition of caspase-3 activation. Intracellular pathogens hijack organelles such as ER to facilitate survival and replication, thus eliciting ER stress and activating/modulating the unfolded protein response (UPR) in the host cell. The UPR is aimed to mitigate ER stress, thereby promoting cell survival. However, prolonged ER stress will activate the apoptotic pathway. The aim of this study was to investigate the ER stress response in Leishmania-infected macrophages to gain insights about the mechanisms underlying the apoptosis resistance in parasitized cells. Macrophages differentiated from human monocytic cell lines (U937 and THP-1) and murine primary macrophages were infected with Leishmania infantum MHOM/TN/80/IPT1 (WHO international reference strain). Several ER stress/autophagy expression markers, as well as cell survival/apoptosis markers (phospho-Akt and cleaved caspase-3) were evaluated by qPCR and/or by western blotting. As ER stress positive control, cells were treated with tunicamycin or dithiothreitol (DTT). The gene expression analyses showed a mild but significant induction of the ER stress/autophagy markers. The western blot analyses revealed that the Leishmania infection induced Akt phosphorylation and significantly inhibited the induction of caspase-3 cleavage, eIF2α phosphorylation and DDIT3/CHOP expression in tunicamycin and DTT treated cells. The mild but significant increase in ER stress expression markers and the delay/attenuation of the effects of ER stress inducers in infected cells support the hypothesis that L. infantum could promote survival of host cells by inducing a mild ER stress response. The host ER stress response could be not only a common pathogenic mechanism among Leishmania species but also a target for development of new drugs.
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Magnani M