BIOLOGIC EFFECTS OF PERTUSSIS ADENYLATE CYCLASE

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，这些策略旨在避免宿主的破坏 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。B.百日咳(及其他 波尔德氏菌)阐述了一种可溶性和高活性的腺苷酸盐 循环酶。我们已经发现这种酶会使哺乳动物细胞完好无损 积累大量的环状AMP，可能是由于 内部化。环状AMP进而解除吞噬细胞的杀菌作用 流程。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 肺泡巨噬细胞缺乏产生活性氧的能力 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。如果细菌 环化酶也能穿透肺细胞，然后极大地升高环磷酸腺苷 可能导致百日咳杆菌患者明显的纤毛功能障碍 感染。本申请中提出的研究旨在进一步 布罗德氏菌诱导的细胞效应的阐明 宿主细胞环化AMP水平。我们还将探讨B。 百日咳腺苷环化酶可能用于有目的地调节 细胞功能的多样性。这些研究的结果应该会有所帮助。 阐明百日咳杆菌感染的发病机制，并可能提供非常 人工操纵细胞环磷酸腺苷的有用工具 浓度。鉴于大量的药物通过 调节环状AMP代谢，使用这种细菌酶可以 代表了一种新的和潜在的强大的药理学模式 对许多细胞功能的操纵。

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.