Carcinoma of the gallbladder (GBC) is the most frequent tumor of the biliary tract. Despite epidemiological studies showing a correlation between chronic infection with Salmonella enterica Typhi/Paratyphi A and GBC, the underlying molecular mechanisms of this fatal connection are still uncertain. The murine serovar Salmonella Typhimurium has been shown to promote transformation of genetically predisposed cells by driving mitogenic signaling. However, insights from this strain remain limited as it lacks the typhoid toxin produced by the human serovars Typhi and Paratyphi A. In particular, the CdtB subunit of the typhoid toxin directly induces DNA breaks in host cells, likely promoting transformation. To assess the underlying principles of transformation, we used gallbladder organoids as an infection model for Salmonella Paratyphi A. In this model, bacteria can invade epithelial cells, and we observed host cell DNA damage. The induction of DNA double-strand breaks after infection depended on the typhoid toxin CdtB subunit and extended to neighboring, non-infected cells. By cultivating the organoid derived cells into polarized monolayers in air-liquid interphase, we could extend the duration of the infection, and we observed an initial arrest of the cell cycle that does not depend on the typhoid toxin. Non-infected intoxicated cells instead continued to proliferate despite the DNA damage. Our study highlights the importance of the typhoid toxin in causing genomic instability and corroborates the epidemiological link between Salmonella infection and GBC.

中文翻译：

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副伤寒沙门氏菌A感染对人原代胆囊细胞的遗传毒性作用。

胆囊癌（GBC）是最常见的胆道肿瘤。尽管流行病学研究显示，肠伤寒沙门氏菌/副伤寒沙门氏菌A和GBC的慢性感染之间存在相关性，但这种致命联系的潜在分子机制仍不确定。鼠血清沙门氏菌鼠伤寒已显示出通过驱动有丝分裂信号传导来促进遗传易感细胞的转化。但是，由于该菌株缺乏人血清型伤寒和副伤寒A产生的伤寒毒素，因此对其的见解仍然有限。特别是，伤寒毒素的CdtB亚基直接诱导宿主细胞中的DNA断裂，可能促进转化。为了评估转化的基本原理，我们使用胆囊类器官作为沙门氏菌的感染模型副伤寒A.在这种模型中，细菌可以侵入上皮细胞，我们观察到宿主细胞DNA的损伤。感染后DNA双链断裂的诱导取决于伤寒毒素CdtB亚基，并延伸至邻近的未感染细胞。通过将类器官来源的细胞培养成气液界面中的极化单层，我们可以延长感染的持续时间，并且观察到细胞周期的初始停滞不依赖于伤寒毒素。尽管DNA受损，但未感染的陶醉细胞仍继续增殖。我们的研究突出了伤寒毒素在引起基因组不稳定方面的重要性，并证实了沙门氏菌感染与GBC之间的流行病学联系。