Critical role of IRF-5 in the development of T helper 1 responses to Leishmania donovani infection.
Critical role of IRF-5 in the development of T helper 1 responses to Leishmania donovani infection.
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DOI：
10.1371/journal.ppat.1001246
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发表时间：
2011-01-06
期刊：
影响因子：
6.7
通讯作者：
Stäger S
中科院分区：
文献类型：
--
作者：
Paun A;Bankoti R;Joshi T;Pitha PM;Stäger S
转录因子干扰素调节因子5（IRF-5）已被证明参与响应于病毒感染和TLR活化的促炎性细胞因子的诱导，并且在先天性炎症反应中起重要作用。在这项研究中，我们使用的内脏利什曼病的实验模型，以探讨IRF-5的作用，在产生的Th 1反应和Th 1型肝肉芽肿的杜氏利什曼原虫感染的小鼠。我们发现，TLR 7介导的IRF-5的激活对于Th 1对L. Donovani在脾脏慢性感染期间。我们还表明，IRF-5缺陷导致的能力，以控制L。Donovani感染在肝脏和较小的肉芽肿的形成。Irf 5-/-小鼠中的肉芽肿的特征在于增加的IL-4和IL-10应答以及伴随的低iNOS表达。总的来说，这些结果确定IRF-5作为一个关键的分子开关的发展Th 1免疫反应后，L。donovani感染，并揭示了IRF-5在iNOS表达调节中的间接作用。 杜氏利什曼原虫是一种寄生虫，目前感染全球1200万人。为了更好地理解为什么这种寄生虫会导致不治之症，我们选择研究免疫系统如何看待L。donovani。免疫系统通过识别病原体特异性表达的分子来识别感染的生物体。这是由细胞表达的一个受体家族完成的，称为Toll样受体（TLR）。当TLR识别病原体时，它导致细胞内的分子链反应，导致细胞因子的释放。干扰素调节因子（IRFs）是这个信号链中非常重要的一部分。我们研究的蛋白质IRF-5已被鉴定为在TLR识别病毒后诱导促炎细胞因子中具有关键作用。然而，它是否在寄生虫病的免疫反应中发挥作用尚未得到研究。在本研究中，我们用L. Donovani的研究，并首次证明IRF-5对于产生对抗这种寄生虫的保护性反应至关重要。这些结果很重要，因为它们有助于我们理解免疫反应对抗L。donovani。
The transcription factor Interferon Regulatory Factor 5 (IRF-5) has been shown to be involved in the induction of proinflammatory cytokines in response to viral infections and TLR activation and to play an essential role in the innate inflammatory response. In this study, we used the experimental model of visceral leishmaniasis to investigate the role of IRF-5 in the generation of Th1 responses and in the formation of Th1-type liver granulomas in Leishmania donovani infected mice. We show that TLR7-mediated activation of IRF-5 is essential for the development of Th1 responses to L. donovani in the spleen during chronic infection. We also demonstrate that IRF-5 deficiency leads to the incapacity to control L. donovani infection in the liver and to the formation of smaller granulomas. Granulomas in Irf5-/- mice are characterized by an increased IL-4 and IL-10 response and concomitant low iNOS expression. Collectively, these results identify IRF-5 as a critical molecular switch for the development of Th1 immune responses following L. donovani infections and reveal an indirect role of IRF-5 in the regulation of iNOS expression. Leishmania donovani is a parasite that currently infects 12 million people around the world. In order to better understand why this parasite causes incurable disease we chose to investigate how the immune system sees L. donovani. The immune system sees infecting organisms by the recognition of molecules that are specifically expressed by pathogens. This is done by a family of receptors expressed by cells called Toll Like Receptors (TLRs). When TLRs recognize a pathogen it leads to a molecular chain reaction within the cell resulting in the release of cytokines. Interferon Regulatory Factors (IRFs) are a very important part of this signaling chain. The protein we have studied, IRF-5, has been identified as having a key role in inducing pro-inflammatory cytokines following the recognition of viruses by TLRs. However, whether it plays a role in the immune response to parasitic disease has not yet been examined. In this study we infected mice deficient of IRF-5 with L. donovani and demonstrate for the first time that IRF-5 is essential to develop a protective response against this parasite. These results are important as they help us to understand the molecular mechanisms required for an immune response to fight L. donovani.
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