Hemophagocytosis induced by Leishmania donovani infection is beneficial to parasite survival within macrophages
Hemophagocytosis induced by Leishmania donovani infection is beneficial to parasite survival within macrophages
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DOI：
10.1371/journal.pntd.0007816
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发表时间：
2019-11-01
影响因子：
3.8
通讯作者：
Goto, Yasuyuki
中科院分区：
文献类型：
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作者：
Morimoto, Ayako;Uchida, Kazuyuki;Goto, Yasuyuki
内脏利什曼病（VL）是由利什曼原虫属的寄生原虫引起的，其特征是临床表现如发热、肝脾肿大和贫血。噬血细胞作用是巨噬细胞吞噬血细胞的现象，存在于VL患者中。在先前的研究中，我们建立了VL的实验模型，第一次在小鼠中复制贫血，并确定了脾脏中严重感染的巨噬细胞的噬血作用是贫血的可能原因。然而，寄生虫诱导的噬血细胞作用的机制或其在寄生虫生存中的作用仍不清楚。在这里，我们建立了一个利什曼原虫诱导的噬血细胞作用的体外模型，以探索参与这一过程的分子。与不摄取新鲜分离的红细胞的原始RAW 264.7细胞（小鼠巨噬细胞系）相反，用L. donovani显示增强的红细胞吞噬作用。此外，对于在体外和体内发现的噬血细胞，信号调节蛋白α（SIRP α）的表达，负责“不要吃我”信号的受体之一，被转录后控制抑制。此外，在给定的巨噬细胞内红细胞和利什曼原虫寄生虫的重叠吞噬作用似乎对寄生虫有益;体外实验显示，在被诱导吞噬红细胞的巨噬细胞内寄生虫的数量更高。总之，这些结果表明，利什曼原虫可能会积极诱导噬血细胞通过操纵SIRP α在巨噬细胞/噬血细胞的表达，以确保其parasitism.Author摘要寄生虫可以操纵宿主的免疫反应，建立有利的环境，他们。由于这种寄生虫驱动的免疫调节通常与感染个体的症状有关，因此不仅杀寄生虫化合物，而且限制这种寄生虫能力的免疫干预也将作为治疗选择。在这项研究中，我们研究了由杜氏利什曼原虫（VL的病原体）引起的噬血细胞作用（巨噬细胞吞噬红细胞的现象）的机制及其作用。体外实验表明，寄生虫能直接破坏巨噬细胞对自身细胞的识别，并能诱导巨噬细胞吞噬红细胞。多诺万尼感染有利于寄生虫的细胞内生存。这些结果表明，利什曼原虫通过操纵巨噬细胞中的“不要吃我”信号来主动诱导噬血细胞作用以使其存活。虽然利什曼原虫如何改变巨噬细胞中的“不要吃我”信号仍有待确定，但我们的研究可能有助于开发一种免疫疗法，该疗法限制了这种变化，并改善了由于噬血细胞作用引起的贫血，以及控制寄生虫的存活。
Visceral leishmaniasis (VL) is caused by parasitic protozoa of the genus Leishmania and is characterized by clinical manifestations such as fever, hepatosplenomegaly and anemia. Hemophagocytosis, the phenomenon of phagocytosis of blood cells by macrophages, is found in VL patients. In a previous study we established an experimental model of VL, reproducing anemia in mice for the first time, and identified hemophagocytosis by heavily infected macrophages in the spleen as a possible cause of anemia. However, the mechanism for parasite-induced hemophagocytosis or its role in parasite survival remained unclear. Here, we established an in vitro model of Leishmania-induced hemophagocytosis to explore the molecules involved in this process. In contrast to naive RAW264.7 cells (mouse macrophage cell line) which did not uptake freshly isolated erythrocytes, RAW264.7 cells infected with L. donovani showed enhanced phagocytosis of erythrocytes. Additionally, for hemophagocytes found both in vitro and in vivo, the expression of signal regulatory protein alpha (SIRP alpha), one of the receptors responsible for the 'don't-eat-me' signal was suppressed by post-transcriptional control. Furthermore, the overlapped phagocytosis of erythrocytes and Leishmania parasites within a given macrophage appeared to be beneficial to the parasites; the in vitro experiments showed a higher number of parasites within macrophages that had been induced to engulf erythrocytes. Together, these results suggest that Leishmania parasites may actively induce hemophagocytosis by manipulating the expression of SIRP alpha in macrophages/hemophagocytes, in order to secure their parasitism.Author summary Parasites can manipulate host immune responses to build favorable environment to them. Because this parasite-driven immune modulation is often linked to symptoms in infected individuals, not only parasiticidal compounds but also immunological interventions limiting such the parasites' abilities will serve as treatment options. In this study, we studied the mechanism and its role of hemophagocytosis (the phenomenon whereby macrophages engulf erythrocytes) caused by Leishmania donovani, a causative agent of VL. In vitro experiments revealed parasites have ability to directly disrupt macrophage's recognition of self-cells, and that the induced engulfment of erythrocytes by L. donovani infection is beneficial to the parasites for their intracellular survival. These results suggest that Leishmania parasites actively induce hemophagocytosis by manipulating the 'don't-eat-me' signal in macrophages for their survival. Although it is still to be determined how Leishmania parasites change the 'don't-eat-me' signal in macrophages, our study may facilitate development of an immunotherapy which limits the change and lead to improvement of anemia due to hemophagocytosis as well as control of parasite survival.