Apolipoprotein E Plays a Key Role against Cryptosporidial Infection in Transgenic Undernourished Mice
Apolipoprotein E Plays a Key Role against Cryptosporidial Infection in Transgenic Undernourished Mice
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DOI：
10.1371/journal.pone.0089562
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发表时间：
2014-02-28
期刊：
影响因子：
3.7
通讯作者：
Guerrant, Richard L.
中科院分区：
文献类型：
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作者：
Azevedo, Orleancio G. R.;Bolick, David T.;Guerrant, Richard L.
载脂蛋白E(ApoE)是脂类平衡的关键靶向蛋白，已被发现在感染和营养不良的小鼠模型中具有免疫炎症效应。ApoE在营养不良和微小隐孢子虫感染的小鼠中的作用尚未被研究。为了研究apoE在微小弧菌感染模型中的作用，我们使用了以下C57BL6J小鼠遗传株：apoE缺陷的野生型对照和表达人apoE基因的apoE靶向替换(Tr)小鼠(E3/3；E4/4)。实验小鼠口服10(7)-Unexysted-C。小卵囊在出生后34-35天之间出现，随后是低蛋白饮食引起的营养不良。小鼠在细小毛滴虫攻击后7天处死，观察回肠形态、细胞因子、阳离子精氨酸转运体(CAT-1)、精氨酸酶1、Toll样受体9(TLR9)和诱导型一氧化氮合酶(INOS)的表达。此外，我们还用qRT-PCR和血脂分析了大便卵囊的脱落情况。与apoE3/3-tr和野生型小鼠相比，apoE4/4-tr小鼠在感染加营养不良后体重增加更好。ApoE4/4-tr和APOE基因敲除小鼠的卵囊脱落较少，但后者表现为绒毛钝化，回肠促炎细胞因子和iNOS转录水平较高。与apoE基因敲除相比，apoE4/4-tr小鼠回肠CAT-1、精氨酸酶-1和TLR9转录增加。虽然有抗寄生虫的作用，但APOE缺乏会加剧营养不良和感染微小毛滴虫的小鼠的肠道炎症反应和粘膜损伤。此外，人类APOE4基因被发现对隐孢子虫感染和营养不良的复合伤害具有保护作用，从而扩展了我们之前关于APOE4儿童预防腹泻的发现。综上所述，我们的研究结果表明apoE在隐孢子虫感染和营养不良的肠道修复和免疫炎症反应中起关键作用。
Apolipoliprotein E (apoE), a critical targeting protein in lipid homeostasis, has been found to have immunoinflammatory effects on murine models of infection and malnutrition. The effects of apoE in undernourished and Cryptosporidium parvum-infected mice have not been investigated. In order to study the role of apoE in a model of C. parvum infection, we used the following C57BL6J mouse genetic strains: APOE-deficient, wild-type controls, and APOE targeted replacement (TR) mice expressing human APOE genes (E3/3; E4/4). Experimental mice were orally infected with 10(7)-unexcysted-C. parvum oocysts between post-natal days 34-35 followed by malnutrition induced with a low-protein diet. Mice were euthanized seven days after C. parvum-challenge to investigate ileal morphology, cytokines, and cationic arginine transporter (CAT-1), arginase 1, Toll-like receptor 9 (TLR9), and inducible nitric oxide synthase (iNOS) expression. In addition, we analyzed stool oocyst shedding by qRT-PCR and serum lipids. APOE4/4-TR mice had better weight gains after infection plus malnutrition compared with APOE3/3-TR and wild-type mice. APOE4/4-TR and APOE knockout mice had lower oocyst shedding, however the latter exhibited with villus blunting and higher ileal pro-inflammatory cytokines and iNOS transcripts. APOE4/4-TR mice had increased ileal CAT-1, arginase-1, and TLR9 transcripts relative to APOE knockout. Although with anti-parasitic effects, APOE deficiency exacerbates intestinal inflammatory responses and mucosal damage in undernourished and C. parvum-infected mice. In addition, the human APOE4 gene was found to be protective against the compounded insult of Cryptosporidium infection plus malnutrition, thus extending our previous findings of the protection against diarrhea in APOE4 children. Altogether our findings suggest that apoE plays a key role in the intestinal restitution and immunoinflammatory responses with Cryptosporidium infection and malnutrition.