Translational profiling of macrophages infected with Leishmania donovani identifies mTOR- and eIF4A-sensitive immune-related transcripts
Translational profiling of macrophages infected with Leishmania donovani identifies mTOR- and eIF4A-sensitive immune-related transcripts
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DOI：
10.1371/journal.ppat.1008291
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发表时间：
2020-06-01
期刊：
影响因子：
6.7
通讯作者：
Jaramillo, Maritza
中科院分区：
文献类型：
--
作者：
Chaparro, Visnu;Leroux, Louis-Philippe;Jaramillo, Maritza
杜氏利什曼原虫（Leishmaniadonovani（L.）donovani）引起内脏利什曼病，这是一种慢性感染，如果不加以治疗是致命的。在此，我们研究了是否除了改变转录，L。donovani调节宿主mRNA翻译以建立成功的感染。多聚体分析显示，在原代小鼠巨噬细胞中表达的三分之一的蛋白编码mRNA在感染L. Donovani前鞭毛体或无鞭毛体。基因本体分析鉴定了富集了受免疫调节的mRNA的关键生物过程，并预测在感染后被激活（例如染色质重塑和RNA代谢）或抑制（例如细胞内运输和抗原呈递）。计算机模拟和生物化学分析显示，选择性激活mTOR和eIF 4A依赖性mRNA翻译，包括编码mRNA周转和炎症的中枢调节因子（即PABPC 1、EIF 2AK 2和TGF-β）的转录物。L.巨噬细胞内的donovani存活在mTOR抑制下是有利的，但被eIF 4A的药理学阻断抑制。总的来说，这项研究揭示了一个巨大的，但选择性的宿主细胞翻译景观早期在L。donovani感染，并表明这些变化中的一些涉及宿主防御机制，而其他的寄生虫驱动的生存策略的一部分。进一步的体外和体内研究将阐明mTOR和eIF 4A依赖性翻译程序对内脏利什曼病结局的贡献。
The protozoan parasite Leishmania donovani (L. donovani) causes visceral leishmaniasis, a chronic infection which is fatal when untreated. Herein, we investigated whether in addition to altering transcription, L. donovani modulates host mRNA translation to establish a successful infection. Polysome-profiling revealed that one third of protein-coding mRNAs expressed in primary mouse macrophages are differentially translated upon infection with L. donovani promastigotes or amastigotes. Gene ontology analysis identified key biological processes enriched for translationally regulated mRNAs and were predicted to be either activated (e.g. chromatin remodeling and RNA metabolism) or inhibited (e.g. intracellular trafficking and antigen presentation) upon infection. Mechanistic in silico and biochemical analyses showed selective activation mTOR- and eIF4A-dependent mRNA translation, including transcripts encoding central regulators of mRNA turnover and inflammation (i.e. PABPC1, EIF2AK2, and TGF-beta). L. donovani survival within macrophages was favored under mTOR inhibition but was dampened by pharmacological blockade of eIF4A. Overall, this study uncovers a vast yet selective reprogramming of the host cell translational landscape early during L. donovani infection, and suggests that some of these changes are involved in host defense mechanisms while others are part of parasite-driven survival strategies. Further in vitro and in vivo investigation will shed light on the contribution of mTOR- and eIF4A-dependent translational programs to the outcome of visceral leishmaniasis.