Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular pathogen that damages gastrointestinal tissue and causes severe diarrhoea. The mechanisms by which Salmonella disrupts epithelial barrier and increases the paracellular permeability are incompletely understood. Our present study aims to determine the role of Gli1, a transcription factor activated in the sonic hedgehog (Shh) pathway, in decreasing the levels of apical junction proteins in a Salmonella ‐infected human colonic epithelial cancer cell line, Caco‐2, and in the intestinal tissue of Salmonella‐infected mice. Here, we report that S . Typhimurium increased the mRNA and protein levels of Gli1 and Snail, a downstream transcription factor that plays an important role in the epithelial‐to‐mesenchymal transition (EMT). S. Typhimurium also decreased the levels of E‐cadherin and three tight junction proteins (ZO‐1, claudin‐1, and occludin). Gli1 siRNA and GANT61, a Gli1‐specific inhibitor, blocked S. Typhimurium‐induced Snail expression, restored the levels of E‐cadherin and tight junction proteins, and prevented S. Typhimurium‐increased paracellular permeability. Further study showed that Gli1 was cross‐activated by the MAP and PI‐3 kinase pathways. S. Typhimurium devoid of sopB , an effector of the Type 3 secretion system (T3SS) responsible for AKT activation, was unable to induce Snail expression and to decrease the expression of apical junction proteins. Our study uncovered a novel role of Gli1 in mediating the Salmonella ‐induced disruption of the intestinal epithelial barrier.

中文翻译：

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Gli1-Snail 轴有助于鼠伤寒沙门氏菌诱导的肠上皮细胞细胞间连接的破坏。

沙门氏菌血清型鼠伤寒沙门氏菌 ( S. Typhimurium) 是一种兼性细胞内病原体，可损害胃肠道组织并导致严重腹泻。沙门氏菌破坏上皮屏障并增加细胞旁通透性的机制尚不完全清楚。我们目前的研究旨在确定 Gli1（一种在声波刺猬 (Shh) 通路中激活的转录因子）在降低沙门氏菌感染的人结肠上皮癌细胞系 Caco-2中顶端连接蛋白水平方面的作用，以及沙门氏菌感染小鼠的肠道组织。在这里，我们报告S. Typhimurium 增加了 Gli1 和 Snail 的 mRNA 和蛋白质水平，Snail 是一种下游转录因子，在上皮间质转化 (EMT) 中起重要作用。S. Typhimurium 还降低了 E-钙粘蛋白和三种紧密连接蛋白（ZO-1、claudin-1 和 occludin）的水平。GLI1 siRNA和GANT61，一个GLI1特异性抑制剂，阻断S.鼠伤寒沙门氏菌引起的蜗牛表达，恢复E-钙粘蛋白和紧密连接蛋白的水平，并防止了鼠伤寒沙门氏菌，增加细胞旁渗透性。进一步的研究表明，Gli1 被 MAP 和 PI-3 激酶途径交叉激活。S.鼠伤寒缺乏sopB是负责 AKT 激活的 3 型分泌系统 (T3SS) 的效应器，无法诱导 Snail 表达并降低顶端连接蛋白的表达。我们的研究揭示了 Gli1 在介导沙门氏菌引起的肠上皮屏障破坏方面的新作用。