Deng Lingquan, Song Jeongmin, Gao Xiang, Wang Jiawei, Yu Hai, Chen Xi, Varki Nissi, Naito-Matsui Yuko, Galán Jorge E, Varki Ajit
Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA.
Cell. 2014 Dec 4;159(6):1290-9. doi: 10.1016/j.cell.2014.10.057.
Salmonella Typhi is an exclusive human pathogen that causes typhoid fever. Typhoid toxin is a S. Typhi virulence factor that can reproduce most of the typhoid fever symptoms in experimental animals. Toxicity depends on toxin binding to terminally sialylated glycans on surface glycoproteins. Human glycans are unusual because of the lack of CMAH, which in other mammals converts N-acetylneuraminic acid (Neu5Ac) to N-glycolylneuraminic acid (Neu5Gc). Here, we report that typhoid toxin binds to and is toxic toward cells expressing glycans terminated in Neu5Ac (expressed by humans) over glycans terminated in Neu5Gc (expressed by other mammals). Mice constitutively expressing CMAH thus displaying Neu5Gc in all tissues are resistant to typhoid toxin. The atomic structure of typhoid toxin bound to Neu5Ac reveals the structural bases for its binding specificity. These findings provide insight into the molecular bases for Salmonella Typhi's host specificity and may help the development of therapies for typhoid fever.
伤寒杆菌是一种专门感染人类的病原体，可引发伤寒热。伤寒毒素是伤寒杆菌的一种毒力因子，能在实验动物身上重现大部分伤寒热症状。毒性取决于毒素与表面糖蛋白上末端唾液酸化聚糖的结合。人类聚糖不同寻常，因为缺乏胞苷单磷酸-N-乙酰神经氨酸羟化酶（CMAH），而在其他哺乳动物中，该酶可将N-乙酰神经氨酸（Neu5Ac）转化为N-羟乙酰神经氨酸（Neu5Gc）。在此，我们报告伤寒毒素对表达以Neu5Ac结尾的聚糖（由人类表达）的细胞具有结合作用且有毒性，而对表达以Neu5Gc结尾的聚糖（由其他哺乳动物表达）的细胞则不然。因此，在所有组织中都组成性表达CMAH从而显示Neu5Gc的小鼠对伤寒毒素具有抗性。与Neu5Ac结合的伤寒毒素的原子结构揭示了其结合特异性的结构基础。这些发现为伤寒杆菌宿主特异性的分子基础提供了见解，并可能有助于伤寒热治疗方法的开发。
