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首页> 外文期刊>Infection and immunity >Leishmania donovani Amastigotes Impair Gamma Interferon-Induced STAT1α Nuclear Translocation by Blocking the Interaction between STAT1α and Importin-α5
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Leishmania donovani Amastigotes Impair Gamma Interferon-Induced STAT1α Nuclear Translocation by Blocking the Interaction between STAT1α and Importin-α5

机译：Leishmania donovani Amastigotes通过阻断STAT1α和Importin-α5之间的相互作用来损害γ干扰素诱导的STAT1α核易位。

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The protozoan parasite Leishmania donovani, the etiological agent of visceral leishmaniasis, is renowned for its capacity to sabotage macrophage functions and signaling pathways stimulated by activators such as gamma interferon (IFN-γ). Our knowledge of the strategies utilized by L. donovani to impair macrophage responsiveness to IFN-γ remains fragmentary. In the present study, we investigated the impact of an infection by the amastigote stage of L. donovani on IFN-γ responses and signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in mouse bone marrow-derived macrophages. The levels of IFN-γ-induced expression of major histocompatibility complex class II and inducible nitric oxide synthase (iNOS) were strongly reduced in L. donovani amastigote-infected macrophages. As the expression of those genes is mediated by the transcription factors STAT1α and IFN regulatory factor 1 (IRF-1), we investigated their activation in amastigote-infected macrophages treated with IFN-γ. We found that whereas STAT1α protein levels and the levels of phosphorylation on Tyr701 and Ser727 were normal, IRF-1 expression was inhibited in infected macrophages. This inhibition of IRF-1 expression correlated with a defective nuclear translocation of STAT1α, and further analyses revealed that the IFN-γ-induced STAT1α association with the nuclear transport adaptor importin-α5 was compromised in L. donovani amastigote-infected macrophages. Taken together, our results provide evidence for a novel mechanism used by L. donovani amastigotes to interfere with IFN-γ-activated macrophage functions and provide a better understanding of the strategies deployed by this parasite to ensure its intracellular survival.
机译：内脏利什曼病的病原体原生动物寄生虫利什曼原虫donovani，以破坏巨噬细胞功能和被γ-干扰素（IFN-γ）等激活物刺激的信号通路的能力而闻名。我们对多诺氏乳杆菌用来削弱巨噬细胞对IFN-γ响应能力的策略的知识仍然是零碎的。在本研究中，我们调查了小鼠诺曼氏梭状芽孢杆菌的鞭毛体阶段感染对IFN-γ反应和通过Janus激酶（JAK）信号转导子和转录激活子（STAT）通路在小鼠骨髓中的影响。衍生的巨噬细胞。干扰素-γ诱导的主要组织相容性复合物II类和诱导型一氧化氮合酶（iNOS）的表达水平大大降低了多巴尼鞭毛虫感染的巨噬细胞。由于这些基因的表达是由转录因子STAT1α和IFN调节因子1（IRF-1）介导的，因此我们研究了它们在经IFN-γ处理的被鞭毛感染的巨噬细胞中的激活作用。我们发现，尽管STAT1α蛋白水平和Tyr701和Ser727的磷酸化水平正常，但IRF-1表达在感染的巨噬细胞中受到抑制。 IRF-1表达的这种抑制与STAT1α的核易位相关，进一步的分析表明，IFN-γ诱导的STAT1α与核转运适配器importin-α5的结合在多毛尼假单胞菌感染的巨噬细胞中受到损害。综上所述，我们的结果提供了证据，证明了诺瓦氏乳杆菌（L. donovani amastigotes）使用新机制来干扰IFN-γ激活的巨噬细胞功能，并提供了对该寄生虫所采用的确保其细胞内存活的策略的更好理解。

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