Modulation of T cell Responses by Ebola Glycoprotein

埃博拉糖蛋白对 T 细胞反应的调节

• 批准号: 6570789
• 负责人: Hao Shen
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6570789
• 关键词: Ebola virus; T lymphocyte; cell adhesion molecules; cell migration; clinical research; dendritic cells; genetically modified animals; human subject; laboratory mouse; leukocyte activation /transformation; passive immunization; secretory protein; virus protein

DESCRIPTION (provided by applicant): Ebola virus is an emerging human pathogen responsible for outbreaks of severe hemorrhagic fever with mortality rates approaching 90% and represents a potential threat as a bio-terrorism agent. A prominent feature of Ebola virus infection is the lack of an effective immune response, characterized by lymphocyte depletion, suppression of T cell proliferation and little leukocyte infiltration into the sites of infection. The glycoprotein (GP) of Ebola virus has been implicated in causing immunosuppression, although its precise role and the mechanism remain largely unknown. We have recently demonstrated that EBO GP binds to DC-SIGN on the cell surface, leading to enhanced virus attachment and infection of host cells. In addition to the envelope GP, Ebola virus produces a soluble form of glycoprotein (sGP), which also binds to DC-SIGN. Since sGP is not associated with virions, it is unlikely to serve as an attachment factor, and the significance of its binding to the DC surface lectin molecule (DC-SIGN) is not known. DC-SIGN is highly expressed in DCs, which are the most efficient antigen presenting cells for activating naive T cells. DCs are capable of acquiring foreign antigens in the periphery and then trafficking to the secondary lymphoid organs where they present antigens to T cells in the context of major histocompatibility complex (MHC) and multiple co-stimulatory signals. The DC-SIGN molecule plays a role in both processes: 1) it interacts with intercellular adhesion molecule (ICAM)-2 on endothelial cells to facilitate the trafficking of DCs and 2) it interacts with ICAM-3 on T cells to initiate the formation of immunological synapses between DCs and T cells. We hypothesize that Ebola virus sGP, like antibodies to DC-SIGN, may block DC-SIGN interactions with ICAM-2 and/or ICAM-3, thus interfering with the ability of DCs to activate T cells. We will test our hypothesis in an in vitro system to determine whether Ebola virus sGP affects the activation of human T cells by DC-SIGN positive DCs. We will then extend our analysis to the murine model to examine whether Ebola virus glycoprotein interferes with the trafficking of DCs to the secondary lymphoid organs and inhibits the ability of DCs to prime naive antigen-specific T cells in vivo. These results will tell us whether Ebola virus sGP, which is made in abundance, yet has no known function, serves to inhibit T cell activation and thus is partly responsible for the many malfunctions described in immune responses to Ebola virus infection.

描述(申请人提供)：埃博拉病毒是一种新出现的人类病原体，可导致严重出血热的暴发，死亡率接近90%，是一种潜在的生物恐怖主义病原体。埃博拉病毒感染的一个显著特征是缺乏有效的免疫反应，其特征是淋巴细胞耗尽，T细胞增殖受到抑制，感染部位几乎没有白细胞渗透。埃博拉病毒的糖蛋白(GP)被认为与导致免疫抑制有关，尽管其确切的作用和机制在很大程度上仍不清楚。我们最近证明了EBO GP与细胞表面的DC-SIGN结合，导致病毒的附着增强和宿主细胞的感染。除了包膜糖蛋白外，埃博拉病毒还会产生一种可溶性糖蛋白(SGP)，它也能与DC-SIGN结合。由于Sgp不与病毒粒子相关，因此它不太可能作为一种附着因子，而且它与DC表面凝集素分子(DC-SIGN)结合的意义尚不清楚。DC-SIGN在DC中高表达，DC是激活初始T细胞最有效的抗原提呈细胞。DC能够在外周获得外来抗原，然后运输到次级淋巴器官，在那里它们在主要组织相容性复合体(MHC)和多种共刺激信号的背景下将抗原递送给T细胞。DC-SIGN分子在两个过程中发挥作用：1)它与内皮细胞上的细胞间黏附分子(ICAM)-2相互作用，促进DC的转运；2)它与T细胞上的ICAM-3相互作用，启动DC与T细胞之间免疫突触的形成。我们推测，与DC-SIGN抗体一样，埃博拉病毒SGP可能会阻断DC-SIGN与ICAM-2和/或ICAM-3的相互作用，从而干扰DC激活T细胞的能力。我们将在体外系统中测试我们的假设，以确定埃博拉病毒SGP是否影响DC-SIGN阳性DC对人类T细胞的激活。然后，我们将把我们的分析扩展到小鼠模型，以检查埃博拉病毒糖蛋白是否干扰树突状细胞向次级淋巴器官的运输，并抑制树突状细胞在体内启动幼稚抗原特异性T细胞的能力。这些结果将告诉我们，埃博拉病毒SGP是否可以抑制T细胞的激活，从而在一定程度上导致对埃博拉病毒感染的免疫反应中描述的许多故障。SGP是一种丰富的埃博拉病毒SGP，但尚不清楚其功能。