BIOLOGIC EFFECTS OF PERTUSSIS ADENYLATE CYCLASE

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All successful pathogens have evolved strategies which allow survival and replication within the potentially hostile environment of the host. In many cases, the strategies are aimed at avoidance of destruction by host phagocytes. This application concerns a unique device employed by Bordetella spp. for paralyzing phagocytic cells. B. pertussis (and other species of Bordetella) elaborates a soluble and highly active adenylate cyclase. We have found that this enzyme will cause intact mammalian cells to accumulate large quantities of cyclic AMP, probably as a result of internalization. The cyclic AMP, in turn, disarms phagocyte bacteriocidal processes. This unusual phagocyte avoidance strategy may explain several of the peculiar characteristics of Bordetella infections, including the lack of activated oxygen production by alveolar macrophages derived from Bordetella-infected animals and the greatly enhanced susceptibility of Bordetella infected humans to secondary infections. If the bacterial cyclase also penetrates pulmonary cells, then greatly elevated cyclic AMP may cause the ciliary dysfunction evident in victims of B. pertussis infection. The research proposed in this application is aimed at further elucidation of the cellular effects of Brodetella-induced elevations of host cell cyclic AMP levels. We shall also explore the possibility that B. pertussis adenylate cyclase might be used in the purposeful modulation of a variety of cellular functions. The results of these studies should help elucidate the pathogenesis of B. pertussis infection and may provide a very useful tool for the artificial manipulation of cellular cyclic AMP concentrations. In view of the great number of drugs which act through modulation of cyclic AMP metabolism, the use of this bacterial enzyme may represent a novel and potentially powerful mode of pharmacologic manipulation of many cellular functions.