Thrombocyte Regulation of Anti-Parasite Immunity

利什曼原虫的寄生虫感染是一种众所周知的慢性炎症性疾病。vt.在.的基础上 在感染/损伤时，白细胞被招募到受影响的部位，并进一步极化。WNT的激活 信号转导可能是维持组织动态平衡和组织修复的最初分子反应之一。它 众所周知，血小板在这些过程中起着重要的作用。虽然慢性炎症在寄生虫中 感染是宿主免疫系统和寄生虫不断相互作用的结果，如何 由寄生虫感染引发和调节的慢性免疫反应仍然难以捉摸。重要的是 这一提议的见解是，血小板释放大量的Wnt拮抗剂Dickkopf-1 (DKK-1)在寄生虫识别和如此高水平的DKK-1调节多个水平的 免疫反应，支持慢性炎症。因此，这一系列事件有利于寄生虫 在宿主中的存活和持续的免疫病理学。DKK-1的这种系统性增加对 免疫系统导致慢性TH2免疫反应的发展和IL-10的增强。 重要的是，在TH1条件下发育的CD4T细胞被驱向TH2(IL-4、IL-13、IL-10) DKK-1存在时的表型。我们提出了两个目标来研究血小板/DKK-1之间的相互作用 利什曼病的几个关键点--宿主先天和获得性免疫反应。第一个目标是， DKK-1从血小板释放的机制将被阐述。由于激活依赖于TLR2， 缺乏表面毒力因子的利什曼原虫突变体将被利用。鉴于已知的 中性粒细胞在利什曼原虫感染中的重要性，我们还将通过 其中DKK-1增加白细胞-血小板聚集(LPA)，并将白细胞招募到感染部位。这个 第二个目的是专门探讨LRP6的CD4T细胞条件缺失的后果， DKK-1和c-Maf的受体以及中性粒细胞中IL-10和LRP6的受体缺失。我们的目标是 探讨血小板、CD4T细胞和中性粒细胞中这些因子在寄生虫感染中的作用 导致疾病易感性或未能激发导致持续感染的无菌免疫。已被占用 总之，这一建议将为理解寄生虫识别和 在感染和随后的致病过程中逃避。我们的建议主要集中在调查 宿主病原菌激发和维持过度旺盛免疫反应的机制 互动。由于我们提出了血小板衍生的DKK-1在调节免疫反应中的多方面作用(S)， 我们的研究将确定血小板在利什曼病中的重要作用，并为开发DKK-1和 利什曼病和潜在其他感染性疾病有效靶点的相关生物途径 疾病。

Parasitic infection by Leishmania is a well-known example of a chronic inflammatory disease. Upon infection/injury, leukocytes are recruited to the affected site, and further polarized. The activation of Wnt signaling is possibly one of the initial molecular responses to maintain tissue homeostasis and tissue repair. It is known that platelets are important players in these processes. Although chronic inflammation in parasitic infection is a consequence of constant interaction between the host immune system and parasites, how chronic immune responses are elicited and modulated by parasitic infection remains elusive. The important insight of this proposal is that platelets release significant amounts of the Wnt antagonist Dickkopf-1 (Dkk-1) following parasite recognition and such elevated levels of Dkk-1 regulate multiple levels of the immune response to support chronic inflammation. Consequently, this sequence of events favors parasite survival and constant immunopathology in the host. This systemic increase in Dkk-1 has potent effects on the immune system leading to the development of chronic TH2 immune responses and a potentiation of IL-10. Importantly, CD4 T cells developing under TH1 conditions were driven towards a TH2 (IL-4, IL-13, IL-10) phenotype in the presence of Dkk-1. We propose two aims to examine the interplay between platelets/Dkk-1 at several pivotal points of Leishmania-host innate and adaptive immune responses. In the first aim, the mechanisms by which Dkk-1 is released from platelets will be addressed. As activation is TLR2 dependent, Leishmania mutants that lack characterized surface virulence factors will be utilized. Given the known importance of PMN leukocytes (neutrophils) in Leishmania infection, we will also address the mechanism by which Dkk-1 increases leukocyte-platelet aggregates (LPA) and recruits leukocytes to the infection site. The second aim will specifically probe the consequences of conditional deletion in CD4 T cells of LRP6, the receptor for Dkk-1, and c-Maf and in neutrophils deletion of the receptor for IL-10 and LRP6. The goal is to investigate the contribution of these factors in platelets, CD4 T cells and neutrophils in parasitic infection leading to disease susceptibility or a failure to elicit sterile immunity that results in persistent infection. Taken together, this proposal will provide novel biological insight towards understanding parasitic recognition and evasion during infection and consequent pathogenesis. Our proposal has a primary focus on investigating the mechanism by which overexuberant immune responses are elicited and maintained by host-pathogen interaction. Since we propose multifaceted role(s) of platelet-derived Dkk-1 in modulating immune responses, our study will identify important roles of platelets in leishmaniasis, and contribute to developing Dkk-1 and related biological pathways as effective therapeutic targets in leishmaniasis and potentially other infectious diseases.