Polyamines and Pneumocystis

描述（由申请方提供）：在肺孢子虫肺炎（PcP）期间，肺泡巨噬细胞（AM）的数量福尔斯下降，损害先天免疫系统。这种缺陷主要是由于细胞内多胺水平升高引起的细胞凋亡率增加。初步结果表明，鸟氨酸脱羧酶，抗酶抑制剂，多胺氧化酶，参与多胺合成和catalysts的水平在感染过程中增加。抗酶抑制剂（AZI）的表达增加导致多胺产生和摄取增加，从而提高细胞内多胺和活性氧（ROS）水平。ROS损伤AM的线粒体，导致细胞凋亡。该项目的中心假设是，防止细胞内多胺水平的增加将提高AM的活力，导致更有效的生物体清除。本项目的长期目标是了解PcP的发病机制，并开发防止AM发生凋亡的方法，从而提高宿主抵抗感染的能力。为了实现这一目标，将确定肺孢子虫（Pc）诱导AZI过表达的机制。初步数据表明，Pc细胞壁成分刺激AM增加AZI表达。将进行进一步的调查，以表征Pc 2-葡聚糖，Pc细胞壁的主要成分，在诱导AZI过表达的作用。其他Pc成分，如主要表面糖蛋白或甘露聚糖，参与Pc诱导的AZI过表达的可能性也将被检查，并将识别将信号传递到AM导致AZI过表达的巨噬细胞受体。 公共卫生相关性：肺孢子虫是艾滋病患者最常见的机会致病菌，它诱导肺泡巨噬细胞凋亡，以增加其在免疫功能低下的宿主中生存和繁殖的机会。这是通过增加多胺的产生和摄取，从而提高肺泡巨噬细胞中的多胺水平来实现的。这项研究将探讨肺孢子虫增加肺泡巨噬细胞中多胺水平的机制。

DESCRIPTION (provided by applicant): During Pneumocystis pneumonia (PcP), the number of alveolar macrophages (AMs) falls, impairing the innate immune system. This defect is mainly due to increased rate of apoptosis caused by elevated levels of intracellular polyamines. Preliminary results indicate that the levels of ornithine decarboxylase, antizyme inhibitor, and polyamine oxidase that are involved in polyamine synthesis and catabolism are increased during the infection. Increased expression of antizyme inhibitor (AZI) leads to increased polyamine production and uptake, thus raising intracellular polyamine and reactive oxygen species (ROS) levels. ROS damage the mitochondria of AMs, resulting in apoptosis. The central hypothesis of this project is that preventing the increase in intracellular polyamine levels will improve the vitality of AMs, leading to a more effective organism clearance. The long-term goal of this project is to understand the mechanism of pathogenesis of PcP and to develop methods to prevent AMs from undergoing apoptosis, thus enhancing the ability of the host to defend against the infection. To achieve this goal, the mechanism by which Pneumocystis (Pc) induces AZI over-expression will be determined. Preliminary data suggest that Pc cell wall components stimulate AMs to increase AZI expression. Further investigations will be performed to characterize the role of Pc 2-glucan, the major component of the Pc cell wall, in the induction of AZI over-expression. The possibility that other Pc components, such as major surface glycoprotein or mannan, are involved in Pc-induced AZI over-expression will also be examined, and macrophage receptors that transmit the signal to AMs leading to AZI over-expression will be identified. PUBLIC HEALTH RELEVANCE: Pneumocystis, the most common opportunistic pathogen in AIDS patients, induces alveolar macrophage apoptosis in order to increase its chance of survival and reproduction in immunocompromised hosts. This is achieved by increasing the production and uptake of polyamines thus raising polyamine levels in alveolar macrophages. The proposed research will investigate the mechanisms by which Pneumocystis increases polyamine levels in alveolar macrophages.