Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
Nature. 2013 Jul 18;499(7458):350-4. doi: 10.1038/nature12377. Epub 2013 Jul 10.
Salmonella enterica serovar Typhi (S. 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 find that the systemic administration of typhoid toxin, a unique virulence factor of S. Typhi, reproduces many of the acute symptoms of typhoid fever in an animal model. We identify 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 co-opted 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.
肠道沙门氏菌血清型 Typhi（S. Typhi）与大多数其他沙门氏菌不同，它会导致一种危及生命的全身性感染，称为伤寒。其独特临床表现的分子基础尚不清楚。在这里，我们发现伤寒毒素（S. Typhi 的一种独特毒力因子）的全身给药可在动物模型中再现伤寒的许多急性症状。我们确定了特定表面糖蛋白上的特定碳水化合物部分作为伤寒毒素的受体，这解释了其广泛的细胞靶特异性。我们展示了伤寒毒素的原子结构，它显示出前所未有的 A2B5 组织，两个共价连接的 A 亚基与五聚体 B 亚基非共价结合。该结构深入了解了毒素的受体结合特异性和输送机制，并揭示了两种强大毒素的活性如何被共同利用到一种独特的毒素中，这种毒素可以引起许多特征性的伤寒症状。这些发现可能会导致针对伤寒的潜在救生疗法的发展。
