Mucosal adjuvant properties of mutant LT-IIa and LT-IIb enterotoxins that exhibit altered ganglioside-binding activities.
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.
Nawar
Hesham F
HF
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, USA.
Arce
Sergio
S
Russell
Michael W
MW
Connell
Terry D
TD
D000276:Adjuvants, Immunologic; D000281:Administration, Intranasal; D000311:Adrenal Glands / Q000166:cytology; D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000633:toxicity; D002460:Cell Line; D004768:Enterotoxins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000633:toxicity; D004926:Escherichia coli / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000633:toxicity; D005260:Female; D005732:Gangliosides / Q000378:metabolism*; D005818:Genetic Engineering; D018928:Immunity, Mucosal; D007114:Immunization; D008264:Macrophages / Q000166:cytology; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D013295:Streptococcus mutans / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D005732:Gangliosides; D008565:Membrane Proteins; C027538:heat-labile enterotoxin, E coli
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