BACTERIAL DEFENSES AGAINST PHAGOCYTE OXIDATIVE KILLING

吞噬细胞具有多种破坏机制， 入侵的生物。 一条重要的攻击线涉及 活性氧物质及其衍生物的产生 (such如卤素）。 这些会破坏各种微生物成分 并帮助摧毁入侵的有机体。 的重要性 氧化剂杀灭细菌的实验强调， 性质如慢性肉芽肿性疾病， 髓过氧化物酶缺乏症 在前一种情况下，最初的失败- 氧的电子还原使吞噬细胞不能进行任何 氧化剂杀死的形式。 因此，受影响的患者 经常感染需氧过氧化氢酶阳性 细菌 髓过氧化物酶活性缺乏的罕见患者 也可能受到感染，但风险不那么严重。 最后，氧化杀伤的失败可能是最重要的， 一群精英病原体占据了 正常吞噬体的特殊生态环境。 生物体 利什曼原虫、军团菌和分枝杆菌可以存活， 在巨噬细胞/单核细胞吞噬空泡内复制， 从而获得保护，不被承认和破坏， 宿主中性粒细胞、抗体和补体。 我们的调查是为了探索一个假设， 这些生物的生存部分取决于它们的 过度氧化防御机制。 的重要性 病原体氧化防御参数的变化并不好 定义了 利用基因改造的细菌 更高或更低的氧化防御活动-包括 超氧化物歧化酶，过氧化氢酶，谷胱甘肽-我们将 确定这些方面的不足和过度的影响， 系统对细菌在暴露于 氧化剂如O2-、过氧化氢和HCl。 并行 研究，我们将确定吞噬细胞破坏的难易程度， 有机体。 这些实验将首次允许， 直接评估病原体氧化防御的重要性 机制等 结果不仅会改善我们的 了解吞噬细胞氧化剂破坏机制， 也提供了线索，在自然进化的必要步骤， 吞噬细胞内致病微生物。

Phagocytic cells possess multiple mechanisms for the destruction of invading organisms. One important line of attack involves the generation of activated oxygen species and derivatives thereof (such as halogens). These damage various microbial components and aid in destruction of the invading organism. The importance of oxidant killing of bacteria is emphasized by experiments of nature such as chronic granulomatous disease and myeloperoxidase deficiency. In the former, failure of initial one- electron reduction of oxygen renders phagocytes incapable of any form of oxidant killing. Consequently, affected patients are subject to frequent infection with aerobic catalase-positive bacteria. Rare patients deficient in myeloperoxidase activity may also be subject to infection but are not so severely at risk. Finally, the failure of oxidative killing may be most important in the case of an elite group of pathogens which occupy the extraordinary econiche of the normal phagosome. Organisms such as Leishmania, Legionella, and Mycobacter may survive and replicate within macrophage/monocyte phagocytic vacuoles, thereby gaining protection from recognition and destruction by host neutrophils, antibodies, and complement. Our investigations are meant to explore the hypothesis that survival of these organisms depends, in part, upon their having hypertrophied oxidant defense mechanisms. The importance of variations in pathogen oxidant defense parameters is not well defined. Employing bacteria genetically manipulated to have higher or lower activities of oxidant defenses - including superoxide dismutase, catalase, and glutathione - we shall determine the effects of deficiencies and excesses in these systems on the ability of the bacteria to survive exposure to oxidants such as 02-, hydrogen peroxide and H0C1. In concurrent studies, we shall determine the ease of phagocyte destruction of the organisms. These experiments will permit, for the first time, direct assessment of the importance of pathogen oxidant defense mechanisms. The results should not only improve our understanding of phagocyte oxidant destruction mechanisms but also provide clues as to necessary steps in the natural evolution of intraphagocytic pathogenic organisms.