Candida albicans infection leads to barrier breakdown and a MAPK/NF-B mediated stress response in the intestinal epithelial cell line C2BBe1
Candida albicans infection leads to barrier breakdown and a MAPK/NF-B mediated stress response in the intestinal epithelial cell line C2BBe1
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DOI：
10.1111/cmi.12566
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发表时间：
2016-07-01
影响因子：
3.4
通讯作者：
Kurzai, Oliver
中科院分区：
文献类型：
--
作者：
Boehringer, Michael;Pohlers, Susann;Kurzai, Oliver
肠上皮细胞（IEC）形成肠腔的紧密屏障。肠屏障的细胞旁通透性由紧密连接蛋白调节，并且可以由微生物和其他刺激物调节。多态性真菌白色念珠菌是人类粘膜的常见寄生菌，具有穿越这一屏障并在宿主内建立系统性疾病的能力。极化的C2BBe 1 IEC感染野生型C.白色念珠菌导致跨上皮电阻（TEER）的短暂增加，随后的屏障破坏，伴随着连接蛋白水平的强烈下降和大量的，但相当延迟的细胞毒性。基于时间分辨芯片的C.白念珠菌攻击的IEC揭示了NF-B和MAPK信号通路在感染应答中的重要作用。因此，我们推断出一个基因调控网络的基础上差异表达的NF-B和MAPK通路的组件和预测的转录靶点。实验验证了预测NF-B激活GDF 15的网络模型。抑制C.白色念珠菌感染C2BBe 1细胞导致上皮细胞的细胞毒性增强。综上所述，我们的研究确定NF-B活化作为上皮细胞对C反应的重要保护性信号通路。白色念珠菌
Intestinal epithelial cells (IEC) form a tight barrier to the gut lumen. Paracellular permeability of the intestinal barrier is regulated by tight junction proteins and can be modulated by microorganisms and other stimuli. The polymorphic fungus Candida albicans, a frequent commensal of the human mucosa, has the capacity of traversing this barrier and establishing systemic disease within the host. Infection of polarized C2BBe1 IEC with wild-type C. albicans led to a transient increase of transepithelial electric resistance (TEER) before subsequent barrier disruption, accompanied by a strong decline of junctional protein levels and substantial, but considerably delayed cytotoxicity. Time-resolved microarray-based transcriptome analysis of C. albicans challenged IEC revealed a prominent role of NF-B and MAPK signalling pathways in the response to infection. Hence, we inferred a gene regulatory network based on differentially expressed NF-B and MAPK pathway components and their predicted transcriptional targets. The network model predicted activation of GDF15 by NF-B was experimentally validated. Furthermore, inhibition of NF-B activation in C. albicans infected C2BBe1 cells led to enhanced cytotoxicity in the epithelial cells. Taken together our study identifies NF-B activation as an important protective signalling pathway in the response of epithelial cells to C. albicans.