Viruses are present in the intestinal microflora and are currently discussed as a potential causative mechanism for the development of inflammatory bowel disease. A number of viruses, such as Human Herpesvirus-8, express homologs to cellular FLIPs, which are major contributors for the regulation of epithelial cell death. In this study we analyzed the consequences of constitutive expression of HHV8-viral FLIP in intestinal epithelial cells (IECs) in mice. Surprisingly, expression of vFlip disrupts tissue homeostasis and induces severe intestinal inflammation. Moreover vFlip^IEC-tg mice showed reduced Paneth cell numbers, associated with excessive necrotic cell death. On a molecular level vFlip expression altered classical and alternative NFκB activation. Blocking of alternative NFκB signaling by deletion of Ikka in vivo largely protected mice from inflammation and Paneth cell loss induced by vFLIP. Collectively, our data provide functional evidence that expression of a single viral protein in IECs can be sufficient to disrupt epithelial homeostasis and to initiate chronic intestinal inflammation.

中文翻译：

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在上皮细胞中表达病毒 Flip 的小鼠慢性肠道炎症。

病毒存在于肠道微生物群中，目前被讨论为炎症性肠病发展的潜在致病机制。许多病毒，如人类疱疹病毒 8，表达细胞 FLIP 的同系物，这是调节上皮细胞死亡的主要因素。在这项研究中，我们分析了 HHV8-病毒 FLIP 在小鼠肠上皮细胞 (IEC) 中组成型表达的后果。令人惊讶的是，vFlip 的表达会破坏组织稳态并诱发严重的肠道炎症。此外 vFlip ^IEC-tg小鼠显示潘氏细胞数量减少，与过度坏死细胞死亡有关。在分子水平上，vFlip 表达改变了经典和替代 NFκB 激活。通过在体内删除 Ikka 来阻断替代 NFκB 信号传导在很大程度上保护了小鼠免受 vFLIP 诱导的炎症和潘氏细胞损失。总的来说，我们的数据提供了功能性证​​据，表明 IEC 中单一病毒蛋白的表达足以破坏上皮稳态并引发慢性肠道炎症。