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Infection and Immunity, December 2000, p. 6903-6911, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Cellular Internalization of Cytolethal Distending Toxin from Haemophilus ducreyi

Ximena Cortes-Bratti,1 Esteban Chaves-Olarte,1 Teresa Lagergård,2 and Monica Thelestam1,*

Microbiology and Tumorbiology Center, Karolinska Institutet, S-171 77 Stockholm,1 and Department of Medical Microbiology and Immunology, University of Gothenburg, S-413 46 Gothenburg,2 Sweden

Received 8 June 2000/Returned for modification 28 August 2000/Accepted 9 September 2000

The chancroid bacterium Haemophilus ducreyi produces a toxin (HdCDT) which is a member of the recently discovered family of cytolethal distending toxins (CDTs). These protein toxins prevent the cyclin-dependent kinase cdc2 from being activated, thus blocking the transition of cells from the G2 phase into mitosis, with the consequent arrest of intoxicated cells in G2. It is not known whether these toxins act by signaling from the cell surface or intracellularly only. Here we report that HdCDT has to undergo at least internalization before being able to act. Cellular intoxication was inhibited (i) by removal of clathrin coats via K+ depletion, (ii) by treatment with drugs that inhibit receptor clustering into coated pits, and (iii) in cells genetically manipulated to fail in clathrin-dependent endocytosis. Intoxication was also completely inhibited in cells treated with bafilomycin A1 or nocodazole and in cells incubated at 18°C, i.e., under conditions known to block the fusion of early endosomes with downstream compartments. Moreover, disruption of the Golgi complex by treatment with brefeldin A or ilimaquinone blocked intoxication. In conclusion, our data indicate that HdCDT enters cells via clathrin-coated pits and has to be transported via the Golgi complex in order to intoxicate cells. This is the first member of the family of CDTs for which cellular internalization and some details of the pathway have been demonstrated.

* Corresponding author. Mailing address: Microbiology and Tumorbiology Center (MTC), Karolinska Institutet, Box 280, S-171 77 Stockholm, Sweden. Phone: 46-8-728 71 62. Fax: 46-8-33 15 47. E-mail: monica.thelestam{at}mtc.ki.se.

Infection and Immunity, December 2000, p. 6903-6911, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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