The role of parasitic phosphatidylserine in the infection of human polymophonuclear neutrophil granulocytes (PMN) by Leishmania major

寄生磷脂酰丝氨酸在重大利什曼原虫感染人多核中性粒细胞（PMN）中的作用

• 批准号: 21110843
• 负责人: Professor Dr. Ger van Zandbergen
• 金额: --
• 依托单位: Abteilung Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2005
• 资助国家: 德国
• 起止时间: 2004-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/21110843?language=en
• 关键词: role; parasitic; phosphatidylserine; infection; human

The obligate intracellular pathogen Leishmania major (L. major) uses phagocytes as host cells. To establish a productive infection phagocyte defenses are inactivated. For multiplication the parasite uses its final host cell, the macrophage. However, before reaching its final destination L. major first recruits and infects polymorphonuclear neutrophil granulocytes (PMN). Infected apoptotic PMN are then used by the parasite as transport vehicle to enter macrophages. Consequently, PMN defenses have to be inactivated first to enable parasite survival. The best example of a non inflammatory entry into phagocytes is the uptake of apoptotic cells. Immune responses are suppressed by the recognition of phosphatidyl serine (PS) expressed on the outer membrane of apoptotic cells. We found that infective promastigotes populations taken either from in vitro cultures or from the sand fly vector contain apoptotic PS-positive parasites. In vivo, in a cutaneous infection model susceptible BALB/c mice infected with purified PS-negative parasites did not develop disease. Disease development depended on the presence of PS-positive parasites. These data suggest that PS is a key mediator in disease development. In vitro, PS-positive parasites enable survival of PS-negative parasites in PMN by a still unknown mechanism. In this project, our main objective will be to elucidate the mechanism of PS-mediated suppression of PMN activation. We will compare PS expression on promastigotes with apoptotic cells. We will study the molecules involved in both PS-dependent and PS-independent uptake of parasites by PMN. In the absence or presence of PS-positive parasites, we will assess PMN immune responses towards viable PS-negative parasites. Finally we will generate a mutant parasite strain unable to express PS. Our investigations will help to understand the pathophysiological mechanisms of Leishmania infections and may provide the base for new therapeutic strategies

专性胞内病原体硕大利什曼原虫（Leishmania major（L. major）使用吞噬细胞作为宿主细胞。为了建立有效的感染，吞噬细胞防御被灭活。为了繁殖，寄生虫使用其最后的宿主细胞，巨噬细胞。然而，在到达最终目的地L之前。主要首先募集并感染多形核中性粒细胞（PMN）。感染的凋亡PMN然后被寄生虫用作运输工具进入巨噬细胞。因此，必须首先灭活PMN防御以使寄生虫存活。非炎症性进入吞噬细胞的最好例子是凋亡细胞的摄取。免疫反应被凋亡细胞外膜上表达的磷脂酰丝氨酸（PS）的识别所抑制。我们发现，无论是在体外培养或从白蛉载体的感染性前鞭毛体人口含有凋亡PS阳性寄生虫。在体内，在皮肤感染模型中，用纯化的PS阴性寄生虫感染的易感BALB/c小鼠未发生疾病。疾病的发展取决于PS阳性寄生虫的存在。这些数据表明，PS是疾病发展的关键介质。在体外，PS阳性的寄生虫使PS阴性的寄生虫在PMN中的生存仍然未知的机制。在这个项目中，我们的主要目标将是阐明PS介导的抑制PMN激活的机制。我们将比较前鞭毛体和凋亡细胞上的PS表达。我们将研究参与PS依赖性和PS非依赖性的PMN吸收寄生虫的分子。在不存在或存在PS阳性寄生虫的情况下，我们将评估PMN对活的PS阴性寄生虫的免疫应答。最后，我们将产生不能表达PS的突变体寄生虫菌株。我们的研究将有助于了解利什曼原虫感染的病理生理机制，并可能为新的治疗策略提供基础