Typhoid fever is a life-threatening disease, but little is known about the molecular bases for its unique clinical presentation. Typhoid toxin, a unique virulence factor of Salmonella Typhi (the cause of typhoid fever), recapitulates in an animal model many symptoms of typhoid fever. Typhoid toxin binding to its glycan receptor Neu5Ac is central, but, due to the ubiquity of Neu5Ac, how typhoid toxin causes specific symptoms remains elusive. Here we show that typhoid toxin displays in vivo tropism to cells expressing multiantennal glycoprotein receptors, particularly on endothelial cells of arterioles in the brain and immune cells, which is in line with typhoid symptoms. Neu5Ac displayed by multiantennal N-glycans, rather than a single Neu5Ac, appears to serve as the high-affinity receptor, as typhoid toxin possesses five identical binding pockets per toxin. Human counterparts also express the multiantennal Neu5Ac receptor. Here we also show that mice immunized with inactive typhoid toxins and challenged with wild-type typhoid toxin presented neither the characteristic in vivo tropism nor symptoms. These mice were protected against a lethal-dose toxin challenge, but Ty21a-vaccinated mice were not. Cumulatively, these results reveal remarkable features describing how a bacterial exotoxin induces virulence exclusively in specific cells at the organismal level.

中文翻译：

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伤寒沙门氏菌毒素对表达多触角聚糖受体的细胞的体内趋向性。


伤寒是一种危及生命的疾病，但对其独特临床表现的分子基础知之甚少。伤寒毒素是伤寒沙门氏菌（伤寒的病因）的独特毒力因子，在动物模型中重现了伤寒的许多症状。伤寒毒素与其聚糖受体 Neu5Ac 的结合是核心，但由于 Neu5Ac 无处不在，伤寒毒素如何引起特定症状仍然难以捉摸。在这里，我们发现伤寒毒素对表达多触角糖蛋白受体的细胞表现出体内趋向性，特别是对大脑小动脉内皮细胞和免疫细胞，这与伤寒症状相符。由多触角 N-聚糖展示的 Neu5Ac，而不是单个 Neu5Ac，似乎充当高亲和力受体，因为伤寒毒素每个毒素具有五个相同的结合袋。人类对应物也表达多触角 Neu5Ac 受体。在这里，我们还表明，用非活性伤寒毒素免疫并用野生型伤寒毒素攻击的小鼠既没有表现出特征性的体内趋向性，也没有表现出症状。这些小鼠受到了致命剂量毒素攻击的保护，但接种 Ty21a 的小鼠却没有。总的来说，这些结果揭示了描述细菌外毒素如何在有机体水平上仅在特定细胞中诱导毒力的显着特征。