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首页> 外文学位 >Transcriptome analysis of host responses to Giardia lamblia infections and identification of novel effector mechanisms in parasite control.
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Transcriptome analysis of host responses to Giardia lamblia infections and identification of novel effector mechanisms in parasite control.

机译：宿主对贾第鞭毛虫感染的应答的转录组分析和寄生虫控制中新型效应器机制的鉴定。

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摘要

As many as one billion cases of infection with Giardia lamblia are thought to occur each year. T cells help control the initial phase of the infection, although the exact mechanisms by which they act are still unknown. Similarly, while B cell-dependent mechanisms contribute to prevention of chronic infections, their role during the early part of the infection remains controversial. In particular, studies suggest Immunoglobulin (Ig) A may not be as crucial in the initial elimination of G. lamblia as they are for G. muris. Antibody-independent mechanisms controlling this infection have not been well-defined. While mast cells participate in the elimination of Giardia, how they are recruited to the site of infection and how they contribute in the elimination of the parasite are not known. We therefore applied microarray technology to profile intestinal gene expression in C57BL/6 mice in response to infection with G. lamblia trophozoites (GS (M)-H7 strain). A total of 96 transcripts were identified as being significantly regulated. Induced transcripts were categorized as coming primarily from B cells and mast cells, consistent with prior knowledge of this infection. Other regulated transcripts suggested activation of Paneth cells and changes in enterocyte function. We further explored the role of two induced transcripts with potential for a role in mucosal immunity: mannose-binding lectin (Mbl2) and matrix metalloproteinase 7 (Mmp7). Wild type mice expressed higher levels of Mmp7 and Mbl2 upon infection compared with uninfected mice. Furthermore, neither transcript was induced following infection of TNF deficient mice, which have a defect in the clearance of Giardia. Mbl-deficient mice showed an inability to recruit mast cells in the intestinal submucosa and were delayed in their elimination of Giardia infection. Mmp7 deficient mice also showed a slightly reduced ability to clear infections. Since nitric oxide has been shown to inhibit parasite growth in vitro but inducible nitric oxide synthase (Nos2) deletion had no effect in vivo, we combined the Mmp7 and Nos2 mutations in double knockout mice. When Mmp7-deficiency was compounded by the absence of Nos2, a significant delay in parasite clearance was observed. These data have identified new mechanisms which contribute to control of Giardia infection in the absence of antibodies. Mbl contributes to parasite control and may aid in the recruitment of mast cells. Mmp7 contributes to production of cryptdin peptides and, along with nitric oxide produced by Nos2, likely represent important factors directly controlling this intestinal pathogen.
机译：每年据估计发生多达十亿例兰氏贾第鞭毛虫感染病例。 T细胞有助于控制感染的初始阶段，尽管它们起作用的确切机制仍不清楚。同样，尽管依赖B细胞的机制有助于预防慢性感染，但它们在感染初期的作用仍存在争议。特别是，研究表明，免疫球蛋白（Ig）A可能在最初消除兰博氏菌中并不像对穆里氏菌一样重要。控制该感染的抗体非依赖性机制尚未明确。尽管肥大细胞参与了贾第鞭毛虫的消除，但是如何将它们募集到感染部位以及它们如何对消除寄生虫起作用。因此，我们将微阵列技术应用于响应G.lamblia滋养体（GS（M）-H7株）感染的C57BL / 6小鼠的肠道基因表达。总共鉴定出96个转录本受到显着调控。诱导的转录本被分类为主要来自B细胞和肥大细胞，与这种感染的先验知识一致。其他受调控的转录本提示Paneth细胞的活化和肠上皮细胞功能的改变。我们进一步探讨了两种诱导的转录本在粘膜免疫中的潜在作用：甘露糖结合凝集素（Mbl2）和基质金属蛋白酶7（Mmp7）。与未感染的小鼠相比，野生型小鼠在感染后表达更高水平的Mmp7和Mbl2。此外，在感染了贾第鞭毛虫清除缺陷的TNF缺陷型小鼠后，均未诱导任何转录本。 Mbl缺乏的小鼠表现出无法在肠粘膜下层募集肥大细胞，并且延迟了它们消除贾第鞭毛虫感染的能力。 Mmp7缺陷小鼠清除感染的能力也略有降低。由于一氧化氮已显示可在体外抑制寄生虫生长，但可诱导的一氧化氮合酶（Nos2）缺失在体内没有作用，因此我们在双基因敲除小鼠中组合了Mmp7和Nos2突变。当缺乏Nos2导致Mmp7缺乏症加剧时，观察到寄生虫清除的显着延迟。这些数据已经确定了在没有抗体的情况下有助于控制贾第鞭毛虫感染的新机制。 Mbl有助于寄生虫控制，并可能有助于肥大细胞的募集。 Mmp7有助于产生隐蛋白肽，并与Nos2产生的一氧化氮一起代表直接控制这种肠道病原体的重要因素。

著录项

  • 作者

    Tako-Ayuk, Ernest.;

  • 作者单位

    Georgetown University.;

  • 授予单位 Georgetown University.;
  • 学科 Biology Parasitology.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 146 p.
  • 总页数 146
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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