Structure and function of the Salmonella Typhi chimaeric A(2)B(5) typhoid toxin.
Structure and function of the Salmonella Typhi chimaeric A(2)B(5) typhoid toxin.
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伤寒沙门氏菌与大多数其他沙门氏菌不同，它会引起危及生命的全身感染，称为伤寒。其独特临床表现的分子基础尚不清楚。在这里，我们发现，在动物模型中，全身施用伤寒毒素（伤寒沙门氏菌独特的毒力因子）会重现伤寒的许多急性症状。我们在特定表面糖蛋白上发现了特定的碳水化合物部分，这些糖蛋白充当伤寒毒素的受体，这解释了其广泛的细胞靶标特异性。我们展示了伤寒毒素的原子结构，它显示了前所未有的 A2B5 组织，其中两个共价连接的 A 亚基与五聚体 B 亚基非共价连接。该结构提供了对毒素的受体结合特异性和传递机制的深入了解，并揭示了两种强大毒素的活性如何被合并成一种独特的毒素，这种毒素可以诱发伤寒的许多特征症状。这些发现可能会导致开发出可能挽救生命的伤寒疗法。
Salmonella Typhi differs from most other salmonellae in that it causes a life-threatening systemic infection known as typhoid fever. The molecular bases for its unique clinical presentation are unknown. Here we found that in an animal model, the systemic administration of typhoid toxin, a unique virulence factor of S. Typhi, reproduces many of the acute symptoms of typhoid fever. We identified specific carbohydrate moieties on specific surface glycoproteins that serve as receptors for typhoid toxin, which explains its broad cell target specificity. We present the atomic structure of typhoid toxin, which shows an unprecedented A2B5 organization with two covalently-linked A subunits non-covalently-associated to a pentameric B subunit. The structure provides insight into the toxin’s receptor-binding specificity and delivery mechanisms and reveals how the activities of two powerful toxins have been coopted into a single, unique toxin that can induce many of the symptoms characteristic of typhoid fever. These findings may lead to the development of potentially life-saving therapeutics against typhoid fever.