TOXINS OF PERTUSSIS--ISOLATION, CHARACTERIZATION AND MECHANISMS OF ACTION

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Bordetella pertussis, the microorganisms which cause the disease commonly known as whooping cough, produces several toxins (i.e., pertussis toxin (PT) and heat labile or dermonecrotic toxin) (see project Z01 HD 01306) which appear to play important roles in pathogenesis of the organism. PT, in addition, is a major protective antigen which is a promising candidate for the development of a new acellular pertussis vaccine (see project Z01 HD 01307). The current project concentrates on elucidating the mechanisms by which pertussis toxin interacts with cells and elicits its diverse pharmacologic actions. The initial event in the interaction of PT with cells appears to be a rapid and essentially irreversible binding of toxin to cells. Using the interaction of PT with fetuin as a model, studies have been conducted which identify the carbohydrate structure with which pertussis toxin interacts. The toxic action of PT is mediated by toxin catalyzed transfer of the ADP-ribose moiety from NAD to the adenylate cyclase regulatory component, Ni. This action of PT has been used as a probe to explore the role of Ni in regulation of cell function, with specific emphasis on those cell types involved in immune response. Treatment of lymphoid cells with PT results in diverse responses which establish that in pathogenesis, PT acts to interfere with the immune response. Treatment with PT has been shown to block the production of cytotoxic T-lymphocytes (CTL's) and results in altered production of the interleukins. These studies point to the importance of PT in altering the immune system in a manner which permits the continuance of infection. Studies aimed at elucidation of the regulating pathways, affected by pertussis toxin action, may provide greater insight into the mechanisms which modulate immune response.