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Infection and Immunity, February 2007, p. 621-633, Vol. 75, No. 2
0019-9567/07/$08.00+0     doi:10.1128/IAI.01009-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mutants of Type II Heat-Labile Enterotoxin LT-IIa with Altered Ganglioside-Binding Activities and Diminished Toxicity Are Potent Mucosal Adjuvants{triangledown}

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

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

Received 27 June 2006/ Returned for modification 26 October 2006/ Accepted 9 November 2006

The structure and function LT-IIa, a type II heat-labile enterotoxin of Escherichia coli, are closely related to the structures and functions of cholera toxin and LT-I, the type I heat-labile enterotoxins of Vibrio cholerae and enterotoxigenic Escherichia coli, respectively. While LT-IIa is a potent systemic and mucosal adjuvant, recent studies demonstrated that mutant LT-IIa(T34I), which exhibits no detectable binding activity as determined by an enzyme-linked immunosorbent assay, with gangliosides GD1b, GD1a, and GM1 is a very poor adjuvant. To evaluate whether other mutant LT-IIa enterotoxins that also exhibit diminished ganglioside-binding activities have greater adjuvant activities, BALB/c 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(T14S), LT-IIa(T14I), or LT-IIa(T14D). All three mutant enterotoxins potentiated strong mucosal immune responses that were equivalent to the response promulgated by wt LT-IIa. All three mutant enterotoxins augmented the systemic immune responses that correlated with their ganglioside-binding activities. Only LT-IIa and LT-IIa(T14S), however, enhanced expression of major histocompatibility complex class II and the costimulatory molecules CD40, CD80, and CD86 on splenic dendritic cells. LT-IIa(T14I) and LT-IIa(T14D) had extremely diminished toxicities in a mouse Y1 adrenal cell bioassay and reduced abilities to induce the accumulation of intracellular cyclic AMP in a macrophage cell line.

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

{triangledown} Published ahead of print on 21 November 2006.

Editor: A. D. O'Brien

Infection and Immunity, February 2007, p. 621-633, Vol. 75, No. 2
0019-9567/07/$08.00+0     doi:10.1128/IAI.01009-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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