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Infection and Immunity, March 2005, p. 1343-1349, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1343-1349.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Toll-Like Receptor 2 Mediates Cellular Activation by the B Subunits of Type II Heat-Labile Enterotoxins

George Hajishengallis,1* Richard I. Tapping,2 Michael H. Martin,3 Hesham Nawar,4 Elizabeth A. Lyle,2 Michael W. Russell,4 and Terry D. Connell4

Department of Microbiology, Immunology, and Parasitology and Center of Excellence in Oral and Craniofacial Biology, Louisiana State University Health Sciences Center, New Orleans, Louisiana,1 Department of Microbiology, University of Illinois, Urbana, Illinois,2 Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama,3 Department of Microbiology and Immunology, Witebsky Center for Microbial Pathogenesis and Immunology, University at Buffalo, Buffalo, New York4

Received 24 September 2004/ Returned for modification 26 October 2004/ Accepted 2 November 2004

The type II heat-labile enterotoxins (LT-IIa and LT-IIb) of Escherichia coli have an AB5 subunit structure similar to that of cholera toxin (CT) and other type I enterotoxins, despite significant differences in the amino acid sequences of their B subunits and different ganglioside receptor specificities. LT-II holotoxins and their nontoxic B subunits display unique properties as immunological adjuvants distinct from those of CT and its B subunits. In contrast to type II holotoxins, the corresponding pentameric B subunits, LT-IIaB and LT-IIbB, stimulated cytokine release in both human and mouse cells dependent upon Toll-like receptor 2 (TLR2). Induction of interleukin-1ß (IL-1ß), IL-6, IL-8, or tumor necrosis factor alpha in human THP-1 cells by LT-IIaB or LT-IIbB was inhibited by anti-TLR2 but not by anti-TLR4 antibody. Furthermore, transient expression of TLR1 and TLR2 in human embryonic kidney 293 cells resulted in activation of a nuclear factor-{kappa}B-dependent luciferase gene in response to LT-IIaB or LT-IIbB. Moreover, peritoneal macrophages from TLR2-deficient mice failed to respond to LT-IIaB or LT-IIbB, in contrast to wild-type or TLR4-deficient cells. These results demonstrate that besides their established binding to gangliosides, the B subunits of type II enterotoxins also interact with TLR2. Although a ganglioside-nonbinding mutant (T34I) of LT-IIaB effectively induced cytokine release, a phenotypically similar point mutation (T13I) in LT-IIbB abrogated cytokine induction, suggesting a variable requirement for gangliosides as coreceptors in TLR2 agonist activity. TLR2-dependent activation of mononuclear cells by type II enterotoxin B subunits appears to be a novel mechanism whereby these molecules may exert their immunomodulatory and adjuvant activities.

* Corresponding author. Mailing address: Department of Microbiology, Immunology, and Parasitology, Center of Excellence in Oral and Craniofacial Biology, 1100 Florida Ave., Box 130, New Orleans, LA 70119. Phone: (504) 619-8709. Fax: (504) 670-2736. E-mail: ghajis{at}lsuhsc.edu.

Editor: J. T. Barbieri

Infection and Immunity, March 2005, p. 1343-1349, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1343-1349.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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