PERTUSSIS ADENYLATE CYCLASE: EFFECTS ON BLOOD CELLS

所有成功的病原体都进化出了生存和 在主机的潜在敌对环境中进行复制。 在 在许多情况下，这些策略旨在避免宿主的破坏， 吞噬细胞 本申请涉及一种独特的装置， 博德特氏菌属用来麻痹吞噬细胞 B。百日咳（和其他 Bordetella的一个变种）阐述了一种可溶性和高活性的腺苷酸 环化酶 我们已经发现这种酶，作为内化的结果， 会导致完整的哺乳动物细胞积累大量的环 风机放大器 环腺苷酸，反过来，解除吞噬细胞杀菌过程。 这种不寻常的吞噬细胞回避策略可以解释几个 博德特氏菌感染的特殊特征，包括缺乏 肺泡巨噬细胞的活性氧产生 感染博德特氏菌的动物和 博德特氏菌感染人类继发感染。 研究建议 目的在于进一步阐明细胞效应 博德特氏菌引起的宿主细胞环AMP水平升高。 我们将 也探讨了B.百日咳腺苷酸环化酶可能 用于有目的地调节多种细胞功能。 的 这些研究结果有助于阐明B的发病机制。 百日咳感染，并可能提供一个非常有用的工具，人工 操纵细胞环AMP浓度。 鉴于伟大的 许多药物通过调节环AMP代谢起作用， 使用这种细菌酶可能代表一种新的和潜在的强大的 许多细胞功能的药理学操作方式。

All successful pathogens have evolved strategies which allow survival and replication within the potentially hostile environment of the host. In many cases, these 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. petussis (and other species of Bordetella) elaborates a soluble and higly active adenylate cyclase. We have found that this enzyme, as a result of internalization, will cause intact mammalian cells to accumulate large quantities of cyclic AMP. 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. The Research proposed in this application is aimed at further elucidation of the cellular effects of Bordetella-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.