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H. CAPSULATUM INTERACTIONS WITH MURINE MACROPHAGES

H. 荚膜与鼠巨噬细胞的相互作用

基本信息

批准号：
3141703
负责人：
J RUSSELL LITTLE
金额：
$ 13.89万
依托单位：
JEWISH HOSPITAL OF SAINT LOUIS
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-12-01 至 1992-11-30
项目状态：
已结题

项目摘要

The dimorphic fungus Histoplasma capsulatum (Hc) is one of a small group of organisms whose virulence seems to relate to its ability to survive within the macrophage rather than its avoidance of ingestion. In infected patients as well as experimental animals, the infective form Yeast) of Hc is found only in macrophage. Epidemiological data indicate that histoplasmosis occurs throughout the world but it is endemic in the central U.S. Host resistance to infection with Hc is conferred by cell mediated immunity and macrophage activation is critical if the host is to destroy the ingested fungal organisms. When macrophage encounter many kinds of invading organisms, phagocytosis of the microbe is associated with an abrupt increase in phagocyte O2 consumption, the oxidative burst (OB). This OB results in the formation of a group of powerful toxic oxidizing agents. However, when macro phages ingest Hc yeast in vitro, they fail to respond normally with an OB. This host cell failure may help to account for the ability of this fungal cell to survive and proliferate in host macrophage in vivo. The goals of this project are to elucidate the biochemical reasons for the failure of macrophage to produce an OB in response to the ingestion of Hc Yeast. We will also attempt to determine which macrophage biochemical events are altered by Hc and how these alterations account for the disordered cellular physiology of Hc- containing macrophage. In particular, we will focus on the effects of Hc on macrophage prostaglandin and cAMP synthesis and the phosphoinositide and cAMP-dependent pathways of cellular signal transduction. The effects of certain cytokines (IFN-gamma, TNF-alpha an macrophage stimulating factor) on the Hc-macrophage interaction will also be examined since these agents may be useful in the treatment of certain patients with histoplasmosis.

二型真菌荚膜组织胞浆菌（Hc）是一种小的毒力似乎与其能力有关的一组生物体在巨噬细胞内生存，而不是避免摄入在受感染的病人和实验动物中， HC的感染形式（酵母菌）仅在巨噬细胞中发现。流行病学数据表明，组织胞浆菌病发生在整个但它在美国中部是地方性的。细胞介导的免疫力赋予感染Hc，巨噬细胞的激活是至关重要的，如果主机是破坏摄入的真菌有机体当巨噬细胞遇到多种入侵生物的吞噬作用与随着吞噬细胞O2消耗量的突然增加，突发（OB）。这种OB导致形成一组强毒性氧化剂。但是，当宏摄取在体外培养的酵母中，它们不能正常地对OB作出反应。这宿主细胞的失败可能有助于解释这种能力，真菌细胞在宿主巨噬细胞中存活和增殖。这个项目的目标是阐明生物化学的原因对于巨噬细胞不能产生OB的原因，摄入HC酵母。我们还将试图确定巨噬细胞的生化事件被HC改变，以及这些改变解释了HC的细胞生理学紊乱，含有巨噬细胞。特别是，我们将重点关注 HC对巨噬细胞前列腺素和cAMP合成的影响磷酸肌醇和cAMP依赖的细胞内信号传导途径信号转导某些细胞因子（IFN-γ， TNF-α（一种巨噬细胞刺激因子）对HC-巨噬细胞由于这些试剂可能是有用的，用于治疗某些组织胞浆菌病患者