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Infection and Immunity, March 2005, p. 1330-1342, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1330-1342.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mucosal Adjuvant Properties of Mutant LT-IIa and LT-IIb Enterotoxins That Exhibit Altered Ganglioside-Binding Activities

Hesham F. Nawar,1 Sergio Arce,1 Michael W. Russell,1 and Terry D. Connell1*

Witebsky Center for Microbial Pathogenesis and Immunology and Department of Microbiology and Immunology, University of Buffalo, State University of New York at Buffalo, Buffalo, New York1

Received 2 July 2004/ Returned for modification 24 September 2004/ Accepted 8 November 2004

LT-IIa and LT-IIb, the type II heat-labile enterotoxins of Escherichia coli, are closely related in structure and function to cholera toxin and LT-I, the type I heat-labile enterotoxins of Vibrio cholerae and E. coli, respectively. Recent studies from our group demonstrated that LT-IIa and LT-IIb are potent systemic and mucosal adjuvants. To determine whether binding of LT-IIa and LT-IIb to their specific ganglioside receptors is essential for adjuvant activity, LT-IIa and LT-IIb enterotoxins were compared with their respective single-point substitution mutants which have no detectable binding activity for their major ganglioside receptors [e.g., LT-IIa(T34I) and LT-IIb(T13I)]. Both mutant enterotoxins exhibited an extremely low capacity for intoxicating mouse Y1 adrenal cells and for inducing production of cyclic AMP in a macrophage cell line. BALB/c female mice were immunized by the intranasal route with the surface adhesin protein AgI/II of Streptococcus mutans alone or in combination with LT-IIa, LT-IIa(T34I), LT-IIb, or LT-IIb(T13I). Both LT-IIa and LT-IIb potentiated strong mucosal and systemic immune responses against AgI/II. Of the two mutant enterotoxins, only LT-IIb(T13I) had the capacity to strongly potentiate mucosal anti-AgI/II and systemic anti-AgI/II antibody responses. Upon boosting with AgI/II, however, both LT-IIa(T34I) and LT-IIb(T13I) enhanced humoral memory responses to AgI/II. Flow cytometry demonstrated that LT-IIa(T34I) had no affinity for cervical lymph node lymphocytes. In contrast, LT-IIb(T13I) retained binding activity for T cells, B cells, and macrophages, indicating that this immunostimulatory mutant enterotoxin interacts with one or more unknown lymphoid cell receptors.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 138 Farber Hall, 3435 Main St., Buffalo, NY 14214. Phone: (716) 829-3364. Fax: (716) 829-2158. E-mail: connell{at}acsu.buffalo.edu.

Editor: J. D. Clements

Infection and Immunity, March 2005, p. 1330-1342, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1330-1342.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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