志贺毒素大肠杆菌能引起严重肠道疾病,其致病机制部分是由枯草杆菌酶(subtilase)细胞毒素调控的。
现在,这种毒素的B-亚单元被发现对含有N-羟乙酰神经氨酸的聚糖有很高亲和力。这种糖类不是由人体合成的,而是作为饮食(如红肉和奶品等)一部分消化的,随后进入小肠和肾脏组织。
具有讽刺意味的是,红肉和奶品(N-羟乙酰神经氨酸的丰富来源)也是最常被有毒细菌污染的食物。所以,通过饮食选择,人类可能会在将自己暴露于一种病原体的同时变得对其更加易感,因为他们的身体组织已变得对一种关键毒性因子非常敏感。(生物谷Bioon.com)
生物谷推荐原始出处:
Nature 456, 648-652 (4 December 2008) | doi:10.1038/nature07428
Incorporation of a non-human glycan mediates human susceptibility to a bacterial toxin
Emma Byres1,6, Adrienne W. Paton2,6, James C. Paton2, Jonas C. L?fling3, David F. Smith4, Matthew C. J. Wilce1, Ursula M. Talbot2, Damien C. Chong2, Hai Yu5, Shengshu Huang5, Xi Chen5, Nissi M. Varki3, Ajit Varki3, Jamie Rossjohn1 & Travis Beddoe1
1 Protein Crystallography Unit and ARC Centre of Excellence for Structural and Functional Microbial Genomics, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
2 School of Molecular and Biomedical Science, University of Adelaide, South Australia 5005, Australia
3 Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093-0687, USA
4 Protein-Carbohydrate Interaction Core H, Emory University School of Medicine, Atlanta, Georgia 30322, USA
5 Department of Chemistry, University of California, Davis, California 95616, USA
AB5 toxins comprise an A subunit that corrupts essential eukaryotic cell functions, and pentameric B subunits that direct target-cell uptake after binding surface glycans. Subtilase cytotoxin (SubAB) is an AB5 toxin secreted by Shiga toxigenic Escherichia coli (STEC)1, which causes serious gastrointestinal disease in humans2. SubAB causes haemolytic uraemic syndrome-like pathology in mice3 through SubA-mediated cleavage of BiP/GRP78, an essential endoplasmic reticulum chaperone4. Here we show that SubB has a strong preference for glycans terminating in the sialic acidN-glycolylneuraminic acid (Neu5Gc), a monosaccharide not synthesized in humans. Structures of SubB–Neu5Gc complexes revealed the basis for this specificity, and mutagenesis of key SubB residues abrogated in vitro glycan recognition, cell binding and cytotoxicity. SubAB specificity for Neu5Gc was confirmed using mouse tissues with a human-like deficiency of Neu5Gc and human cell lines fed with Neu5Gc. Despite lack of Neu5Gc biosynthesis in humans, assimilation of dietary Neu5Gc creates high-affinity receptors on human gut epithelia and kidney vasculature. This, and the lack of Neu5Gc-containing body fluid competitors in humans, confers susceptibility to the gastrointestinal and systemic toxicities of SubAB. Ironically, foods rich in Neu5Gc are the most common source of STEC contamination. Thus a bacterial toxin's receptor is generated by metabolic incorporation of an exogenous factor derived from food.