Modulation of T cell Responses by Ebola Glycoprotein

描述（由申请人提供）：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爆发，死亡率接近90%，并且作为生物恐怖主义制剂具有潜在威胁。埃博拉病毒感染的一个突出特征是缺乏有效的免疫反应，其特点是淋巴细胞耗竭，T细胞增殖受到抑制，白细胞很少渗入感染部位。埃博拉病毒的糖蛋白（GP）与引起免疫抑制有关，尽管其确切作用和机制在很大程度上仍不清楚。我们最近证明EBO GP与细胞表面的DC-SIGN结合，导致病毒对宿主细胞的附着和感染增强。除了包膜糖蛋白外，埃博拉病毒还产生一种可溶性糖蛋白（sGP），它也与DC-SIGN结合。由于sGP不与病毒粒子相关，因此不太可能作为附着因子，其与DC表面凝集素分子（DC- sign）结合的意义尚不清楚。DC-SIGN在dc中高度表达，dc是激活初始T细胞最有效的抗原提呈细胞。dc能够在外周获得外源抗原，然后运输到次级淋巴器官，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呈递给T细胞。DC-SIGN分子在这两个过程中都起作用：1)它与内皮细胞上的细胞间粘附分子(ICAM)-2相互作用，促进dc的运输；2)它与T细胞上的ICAM-3相互作用，启动dc和T细胞之间免疫突触的形成。我们假设埃博拉病毒sGP，像DC-SIGN抗体一样，可能阻断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验证我们的假设，以确定埃博拉病毒sGP是否会影响DC-SIGN阳性dc对人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dc向次级淋巴器官的运输，并抑制dc在体内初始抗原特异性T细胞的能力。这些结果将告诉我们，埃博拉病毒sGP是否具有抑制T细胞激活的作用，从而在一定程度上导致了对埃博拉病毒感染的免疫反应中出现的许多故障。

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.