PERTUSSIS ADENYLATE CYCLASE: EFFECTS ON BLOOD CELLS

所有成功的病原体都进化出了允许存活和 在主机的潜在敌意环境中进行复制。在……里面 在许多情况下，这些策略的目的是避免宿主的破坏 吞噬细胞。此应用程序涉及一种由 波尔德氏菌用来麻痹吞噬细胞。百日咳(及其他) 波尔德氏菌的种类)阐述了一种可溶性的、高活性的腺苷 循环酶。我们发现这种酶，作为内化的结果， 会导致完整的哺乳动物细胞积累大量的循环 安培。环状AMP反过来解除吞噬细胞的杀菌过程。 这种不同寻常的避免吞噬细胞的策略可以解释几个 波尔德氏菌感染的特殊特征，包括缺乏 人肺泡巨噬细胞产生活性氧的实验研究 感染波尔德氏菌的动物和极大增强的敏感性 波尔德氏菌使人类感染二次感染。这项研究建议 旨在进一步阐明细胞效应 波氏杆菌诱导的宿主细胞环磷酸腺苷水平的升高。我们会 也探索百日咳杆菌腺苷环化酶可能是 用于有目的地调节各种细胞功能。这个 这些研究的结果将有助于阐明B细胞的发病机制。 百日咳的感染，可能为人工治疗提供一个非常有用的工具 细胞内环磷酸腺苷浓度的调控。鉴于伟大的 通过调节环磷酸腺苷代谢起作用的药物的数量， 这种细菌酶的使用可能代表着一种新的和潜在的强大 许多细胞功能的药理操作模式。

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.