H. CAPSULATUM INTERACTIONS WITH MURINE MACROPHAGES

点击翻译按钮获取中文摘要

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.