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首页> 外文期刊>Infection and immunity >Elevated Levels of the Plasmodium yoelii Homologue of Macrophage Migration Inhibitory Factor Attenuate Blood-Stage Malaria
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Elevated Levels of the Plasmodium yoelii Homologue of Macrophage Migration Inhibitory Factor Attenuate Blood-Stage Malaria

机译：巨噬细胞迁移抑制因子的约氏疟原虫同系物的水平升高减弱了血期疟疾

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The excessive production of proinflammatory cytokines plays a significant role in the pathogenesis of severe malaria. Mammalian macrophage migration inhibitory factor (MIF) (mMIF) is an immune mediator that promotes a sustained proinflammatory response by inhibiting the glucocorticoid-mediated downregulation of inflammation. In addition, Plasmodium parasites also encode a homologue of mammalian MIF that is expressed in asexual-stage parasites. We used the Plasmodium yoelii murine model to study the potential role of parasite-encoded MIF in the pathogenesis of malaria. Antibodies raised against purified, non-epitope-tagged P. yoelii MIF (PyMIF) were used to localize expression in trophozoite- and schizont-stage parasites and demonstrate extracellular release. In vitro, recombinant PyMIF was shown to actively induce the chemotaxis of macrophages but did not induce or enhance tumor necrosis factor alpha (TNF-α) production from peritoneal macrophages. To examine the role of parasite-derived PyMIF in vivo, two transgenic parasite lines that constitutively overexpress PyMIF were generated, one in a nonlethal P. yoelii 17X background [Py17X-MIF(+)] and the other in a lethal P. yoelii 17XL background [Py17XL-MIF(+)]. Challenge studies with transgenic parasites in mice showed that the increased expression of PyMIF resulted in a reduction in disease severity. Mice infected with Py17X-MIF(+) developed lower peak parasitemia levels than controls, while malaria-associated anemia was unaltered. Infection with Py17XL-MIF(+) resulted in a prolonged course of infection and a reduction in the overall mortality rate. Combined, the data indicate that parasite-derived MIF does not contribute significantly to immunopathology but, through its chemotactic ability toward macrophages, may attenuate disease and prolong infection of highly virulent parasite isolates.
机译：促炎细胞因子的过量产生在严重疟疾的发病机理中起重要作用。哺乳动物巨噬细胞迁移抑制因子（MIF）（mMIF）是一种免疫介质，可通过抑制糖皮质激素介导的炎症下调来促进持续的促炎反应。此外，疟原虫寄生虫还编码在无性阶段寄生虫中表达的哺乳动物MIF的同源物。我们使用约氏疟原虫鼠模型研究了寄生虫编码的MIF在疟疾发病机理中的潜在作用。产生了针对纯化的，未标记表位的 P的抗体。 yoelii MIF（ Py MIF）被用于定位滋养体和裂殖体期寄生虫的表达并证明细胞外释放。 在体外中，重组 Py MIF被证明可积极诱导巨噬细胞的趋化性，但不会诱导或增强腹膜巨噬细胞产生肿瘤坏死因子α（TNF-α）。为了检查体内寄生虫来源的 Py MIF 的作用，产生了两个组成性地过表达 Py MIF的转基因寄生虫株，其中一个在非致死性中 P。 yoelii 17X背景[ Py 17X-MIF（+）]，另一个在致命的 P中。 yoelii 17XL背景[ Py 17XL-MIF（+）]。用小鼠中的转基因寄生虫进行的攻击研究表明， Py MIF的表达增加导致疾病严重程度降低。感染了 Py 17X-MIF（+）的小鼠的峰值寄生虫水平低于对照组，而与疟疾相关的贫血却没有改变。用 Py 17XL-MIF（+）感染可延长感染过程并降低总体死亡率。综合来看，数据表明，寄生虫来源的MIF对免疫病理没有明显贡献，但通过其对巨噬细胞的趋化能力，可以减轻疾病并延长高毒力寄生虫分离株的感染。

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