title: Cytolethal distending toxin family members are differentially affected by alterations in host glycans and membrane cholesterol.
abstract: Cytolethal distending toxins (CDTs) are tripartite protein exotoxins produced by a diverse group of pathogenic Gram-negative bacteria. Based on their ability to induce DNA damage, cell cycle arrest, and apoptosis of cultured cells, CDTs are proposed to enhance virulence by blocking cellular division and/or directly killing epithelial and immune cells. Despite the widespread distribution of CDTs among several important human pathogens, our understanding of how these toxins interact with host cells is limited. Here we demonstrate that CDTs from Haemophilus ducreyi, Aggregatibacter actinomycetemcomitans, Escherichia coli, and Campylobacter jejuni differ in their abilities to intoxicate host cells with defined defects in host factors previously implicated in CDT binding, including glycoproteins, and glycosphingolipids. The absence of cell surface sialic acid sensitized cells to intoxication by three of the four CDTs tested. Surprisingly, fucosylated N-linked glycans and glycolipids, previously implicated in CDT-host interactions, were not required for intoxication by any of the CDTs tested. Finally, altering host-cellular cholesterol, also previously implicated in CDT binding, affected intoxication by only a subset of CDTs tested. The findings presented here provide insight into the molecular and cellular basis of CDT-host interactions.
authors.affiliation: Department of Microbiology, University of California, Los Angeles, California 90095, USA.
authors.forename: Aria
authors.initials: A
authors.lastname: Eshraghi
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Maldonado-Arocho
authors.forename: Amandeep
authors.initials: A
authors.lastname: Gargi
authors.forename: Marissa M
authors.initials: MM
authors.lastname: Cardwell
authors.forename: Michael G
authors.initials: MG
authors.lastname: Prouty
authors.forename: Steven R
authors.initials: SR
authors.lastname: Blanke
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Bradley
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000737:chemistry* / Q000235:genetics*; D016466:CHO Cells; D016123:Campylobacter jejuni / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage; D004926:Escherichia coli / Q000378:metabolism; D006017:Glycolipids / Q000737:chemistry; D006090:Gram-Negative Bacteria / Q000378:metabolism; D006191:Haemophilus ducreyi / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D011134:Polysaccharides / Q000737:chemistry*; D011485:Protein Binding
chemical_list: D001427:Bacterial Toxins; D006017:Glycolipids; D011134:Polysaccharides; C067044:cytolethal distending toxin; D002784:Cholesterol
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