Intestinal Epithelial CD98 Directly Modulates the Innate Host Response to Enteric Bacterial Pathogens
Intestinal Epithelial CD98 Directly Modulates the Innate Host Response to Enteric Bacterial Pathogens
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DOI：
10.1128/iai.01388-12
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发表时间：
2013-03-01
影响因子：
3.1
通讯作者：
Merlin, Didier
中科院分区：
文献类型：
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作者：
Charania, Moiz A.;Laroui, Hamed;Merlin, Didier
CD 98是一种II型跨膜糖蛋白，其在肠道炎症期间在肠上皮细胞（IEC）中表达增加。肠致病性大肠杆菌（EPEC）是一种食源性人类病原体，附着于IEC并将效应蛋白直接注入宿主细胞，从而引发炎症反应。在本研究中，我们在体外和离体研究了CD 98和EPEC的相互作用，并检查了在IEC中过表达人CD 98的FVB野生型（WT）和绒毛膜CD 98转基因小鼠（hCD 98 Tg小鼠），并作为体内模型感染啮齿类柠檬酸杆菌。体内研究表明，定位于结肠细胞顶端区域的CD 98过表达增加了C.啮齿类动物在小鼠结肠中，并导致促炎标志物的表达增加和抗炎标志物的表达减少。结肠癌组织中增殖标志物Ki-67和cyclin D1表达明显增高。啮齿类感染的hCD 98 Tg小鼠与WT小鼠相比。离体研究与体内数据相关。用Caco 2-BBE细胞进行的小干扰RNA（siRNA）研究显示EPEC对Caco 2细胞的粘附减少，其中CD 98表达被敲低。体外表面等离子体共振（SPR）实验显示重组hCD 98与EPEC/C之间直接结合。啮齿动物蛋白我们还证明了hCD 98的部分细胞外环足以直接结合EPEC/C。啮齿动物。这些发现证明了CD 98的细胞外环在通过附着和消除（A/E）病原体对肠道感染的先天宿主防御反应中的重要性。
CD98 is a type II transmembrane glycoprotein whose expression increases in intestinal epithelial cells (IECs) during intestinal inflammation. Enteropathogenic Escherichia coli (EPEC) is a food-borne human pathogen that attaches to IECs and injects effector proteins directly into the host cells, thus provoking an inflammatory response. In the present study, we investigated CD98 and EPEC interactions in vitro and ex vivo and examined FVB wild-type (WT) and villin-CD98 transgenic mice overexpressing human CD98 in IECs (hCD98 Tg mice) and infected with Citrobacter rodentium as an in vivo model. In vivo studies indicated that CD98 overexpression, localized to the apical domain of colonic cells, increased the attachment of C. rodentium in mouse colons and resulted in increased expression of proinflammatory markers and decreased expression of anti-inflammatory markers. The proliferative markers Ki-67 and cyclin D1 were significantly increased in the colonic tissue of C. rodentium-infected hCD98 Tg mice compared to that of WT mice. Ex vivo studies correlate with the in vivo data. Small interfering RNA (siRNA) studies with Caco2-BBE cells showed a decrease in adherence of EPEC to Caco2 cells in which CD98 expression was knocked down. In vitro surface plasmon resonance (SPR) experiments showed direct binding between recombinant hCD98 and EPEC/C. rodentium proteins. We also demonstrated that the partial extracellular loop of hCD98 was sufficient for direct binding to EPEC/C. rodentium. These findings demonstrate the importance of the extracellular loop of CD98 in the innate host defense response to intestinal infection by attaching and effacing (A/E) pathogens.