Analysis of Trypanosome-Evoked Depression of Immunity

锥虫和许多原生寄生虫一样，不能合成嘌呤，必须依靠宿主提供这些化合物。快速增长的细胞外血流锥虫（如啮齿动物或非洲锥虫）对宿主游离嘌呤库的需求可能有两种影响之一，要么：(a)将嘌呤从组织部位明显动员到血流中，要么(b)严重消耗正常的循环嘌呤浓度。在任何一种情况下，现有证据表明，显示表面腺苷受体的宿主细胞（特别是淋巴细胞、中性粒细胞、巨噬细胞和血小板）的正常特性和功能都会发生显著改变。本研究的目的是研究小鼠感染肌肉锥虫过程中血液嘌呤浓度的变化以及选定宿主细胞特性和功能的变化。血浆中16种嘌呤的浓度将在两种小鼠（一种是C3H，对肌肉t虫特别敏感，另一种是C57Bl/6，对肌肉t虫的敏感性相对较低）感染和随后恢复的过程中每隔一段时间（用高效液相色谱法）测定。将详细研究最近在锥虫感染小鼠中发现的腺苷脱氨酶（ADA）和嘌呤核苷磷酸化酶（PNP）的脾细胞活性显著（3-5倍）升高。具体而言，将确定：(a)这些酶的刺激是由于血液中嘌呤过多还是缺乏引起的，(b)哪些类型的脾细胞表现出酶活性升高，(c)刺激是否来自寄生虫（或寄生虫衍生物质）对细胞的直接作用，其中酶活性增加或通过另一种宿主细胞间接介导，以及(d)酶水平升高是否与受感染宿主产生免疫反应的能力下降有关。最后，一旦知道了在感染过程中嘌呤的血液浓度是如何变化的，就可以研究选定细胞(b淋巴细胞、t淋巴细胞、中性粒细胞、库普弗细胞和血小板)的体外维持将被探索。这些研究将提供关于锥虫介导的宿主嘌呤浓度改变导致细胞活性改变的机制，并可能有助于解释锥虫成功抵抗宿主免疫反应的机制。

Trypanosomes, like many protozoan parasites, are unable to synthesize purines and must rely on the host to provide those compounds. The demand placed on the host's pool of free purines by a rapidly-growing population of extracellular, bloodstream trypanosomes (such as the rodent or African trypanosomes) may have one of two effects, either: (a) marked mobilizaton of purines from tissue sites into the bloodstream, or (b) serious depletion of the normal, circulating concentrations of purines. In either case, the available evidence suggests that significant alterations of the normal properties and functions of host cells that display surface adenosine receptors would result (especially lymphocytes, neutrophils, macrophages and platelets). The goals of this research are to investigate changes in bloodstream purine concentrations and changes in the properties and functions of selected host cells during the course of murine infections with Trypanosoma musculi. The concentrations of 16 purines in the plasma will be determined (by high performance liquid chromatography) at intervals during the course of infection, and subsequent recovery, of two strains of mice (one, C3H, that is particularly susceptible to T. musculi and another, C57Bl/6, that is considerably less susceptible). The marked (3-5 fold) rise in splenocyte activity of the enzymes, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), which recently has been discovered in trypanosome-infected mice will be studied in detail. Specifically it will be determined: (a) whether or not the stimulation of these enzymes results from an excess or a paucity of purines in the bloodstream, (b) which types of splenic cells display the elevated enzyme activities, (c) whether or not the stimulus comes from direct action of the parasites (or parasite-derived substances) on cells in which the enzyme activity increases or is mediated indirectly through another type of host cell, and (d) whether or not the elevated enzyme levels are associated with depressed capability of infected hosts to generate immune responses. Finally, once it is known how the bloodstream concentrations of purines change during infection, the effects of similar changes in the properties and functions of selected cells (B-lymphocytes, T-lymphocytes, neutrophils, Kupffer cells and platelets) maintained in vitro will be explored. These studies will provide insight concerning the mechanisms through which trypanosome-mediated alterations in host purine concentrations result in altered cellular activities, and may help to explain the success of trypanosomes in resisting the immune responses of their hosts.