Thrombocyte Regulation of Anti-Parasite Immunity

利什曼原虫寄生虫感染是慢性炎症性疾病的一个众所周知的例子。后 在感染/损伤时，白细胞被募集到受影响的部位，并进一步极化。Wnt的激活 信号传导可能是维持组织稳态和组织修复的初始分子反应之一。它 已知血小板在这些过程中是重要的参与者。虽然寄生虫感染的慢性炎症 感染是宿主免疫系统和寄生虫之间不断相互作用的结果， 由寄生虫感染引起和调节的慢性免疫应答仍然是难以捉摸的。重要 该提议的见解是血小板释放显著量的Wnt拮抗剂Dickkopf-1 在寄生虫识别后，Dkk-1的水平升高，并且Dkk-1的这种升高的水平调节寄生虫的多个水平。 免疫反应，以支持慢性炎症。因此，这一系列事件有利于寄生虫 宿主中的存活和恒定的免疫病理学。Dkk-1的这种系统性增加对细胞凋亡具有潜在的影响。 在某些实施方案中，IL-10可以增强免疫系统，导致慢性TH 2免疫应答的发展和IL-10的增强。 重要的是，在TH 1条件下发育的CD 4 T细胞被驱动朝向TH 2（IL-4、IL-13、IL-10）。 在Dkk-1存在下的表型我们提出了两个目的来研究血小板/Dkk-1之间的相互作用， 利什曼原虫宿主先天性和适应性免疫反应的几个关键点。在第一个目标中， 将阐述Dkk-1从血小板释放的机制。由于激活是TLR 2依赖性的， 将使用缺乏特征性表面毒力因子的利什曼原虫突变体。鉴于已知 中性粒细胞在利什曼原虫感染中的重要性，我们还将通过以下方式阐述其机制： 其中Dkk-1增加白细胞-血小板聚集体（LPA）并将白细胞募集到感染部位。的 第二个目标是特异性地探测LRP 6在CD 4 T细胞中条件性缺失的后果， Dkk-1和c-Maf的受体，以及中性粒细胞中IL-10和LRP 6的受体缺失。目标是 研究这些因子在血小板、CD 4 T细胞和中性粒细胞中的作用 导致疾病易感性或未能引发导致持续感染的无菌免疫。采取 总之，这一提议将为理解寄生虫识别提供新的生物学见解， 在感染和随后的发病过程中逃避。我们的建议主要侧重于调查 宿主-病原体引发和维持过度兴奋的免疫反应的机制 互动由于我们提出血小板衍生的Dkk-1在调节免疫应答中的多方面作用， 我们的研究将确定血小板在利什曼病中的重要作用，并有助于开发Dkk-1和 相关生物学途径作为利什曼病和潜在的其他感染性疾病的有效治疗靶点 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.