BIOLOGICAL EFFECTS OF PERTUSSIS TOXIN B-OLIGOMER

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Pertussis is a major cause of childhood morbidity in the developing world and as a result of concerns about pertussis vaccine reactogenicity, has increased in incidence in many areas of the developed world. Pertussis toxin (PT), a major virulence factor of Bordetella pertussis, elicits a variety of effects including lymphocytosis, sensitization to histamine, and enhancement of insulin secretion. Intriguingly, the B or binding component of PT (B-oligomer), which delivers its active portion to target cells, has biological effects of its own, namely calcium mobilization followed by lymphocyte proliferation and platelet aggregation. These actions, which are poorly understood, are independent of the ADP-ribosylation of G- proteins by which PT has the majority of its known effects. Acquisition of more information is important because many acellular pertussis vaccines contain PT in which holotoxin activities are eliminated, but B-oligomer effects are present or enhanced. In this proposal, different preparations of B-oligomer and holotoxin will be evaluated for potency in eliciting B- oligomer effects (lymphocyte proliferation and platelet activation). The second messenger systems involved will be explored and a screen of other cell types will be made for responses to B-oligomer. The receptor for B- oligomer action will be identified and the structural requirements for B- oligomer to elicit its effects will be studied with toxins containing mutations at specific sites. Finally, the relationship between B-oligomer mobilization of calcium and the subsequent intoxication of a target cell by ADP-ribosylation will be investigated. The resultant data will provide a perspective on using B-oligomer as a research tool and will guide its use as an antigen in acellular pertussis vaccine.