Thrombocyte Regulation of Anti-Parasite Immunity

抗寄生虫免疫的血小板调节

• 批准号: 10560466
• 负责人: Alfred LM Bothwell
• 金额: $ 8.28万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-05 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10560466
• 关键词: Address; Affect; Automobile Driving; Back; Biological; Biological Products; Blood Platelets; CD4 Positive T Lymphocytes; Cell Differentiation process; Chemosensitization; Chronic; Clinical; Communicable Diseases; Cutaneous; Cutaneous Leishmaniasis; Cytokine Signaling; Data; Development; Disease; Disease susceptibility; Equilibrium; Event; Failure; Genetic; Goals; Growth; Homeostasis; Hour; Immune Evasion; Immune response; Immune system; Immunity; Immunologics; Impairment; In Vitro; Inbred BALB C Mice; Infection; Inflammation; Injury; Innate Immune Response; Interleukin-10; Interleukin-13; Interleukin-4; Leishmania; Leishmania major; Leishmaniasis; Lesion; Leucocytic infiltrate; Leukocytes; Ligands; LoxP-flanked allele; Lymphocyte; MYD88 deficiency; Macrophage; Measures; Mediating; Megakaryocytes; Molecular; Monitor; Monoclonal Antibodies; Mouse Strains; Mus; Neutrophil Infiltration; Outcome Assessment; Parasites; Parasitic Diseases; Parasitic infection; Pathogenesis; Pathologic; Pathway interactions; Pharmacological Treatment; Phase; Phenotype; Plasmodium falciparum; Platelet Activation; Platelet aggregation; Process; Proliferating; Public Health; Regulation; Role; Route; S100A8 gene; Schistosoma mansoni; Signal Transduction; Site; Source; Sterility; Structure; Surface; Symptoms; T-Lymphocyte; TLR2 gene; Testing; Th2 Cells; Therapeutic; Therapeutic Effect; Time; Tissues; Trypanosoma cruzi; Ulcer; Virulence Factors; Visceral; WNT Signaling Pathway; adaptive immune response; antagonist; chronic infection; chronic inflammatory disease; cytokine; disease phenotype; experimental study; healing; immunopathology; immunoregulation; in vivo; inhibitor; insight; interleukin-10 receptor; mutant; neutrophil; novel; pathogen; peripheral blood; receptor; reconstitution; recruit; response; therapeutic evaluation; therapeutic target; therapeutic vaccine; therapeutically effective; tissue repair

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.

利什曼原虫（Leishmania）的寄生虫感染是慢性炎症性疾病的众所周知的例子。之上 感染/损伤，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 众所周知，血小板是这些过程中的重要参与者。虽然寄生虫慢性炎症 感染是宿主免疫系统与寄生虫之间不断相互作用的结果，如何 慢性免疫反应是由寄生虫感染引起并调节的。重要 该建议的洞察力是血小板释放了大量的Wnt拮抗剂Dickkopf-1 （DKK-1）寄生虫识别和这种升高的DKK-1调节多个水平 对支持慢性炎症的免疫反应。因此，这一系列事件有利于寄生虫 宿主中的生存和恒定免疫病理学。 DKK-1的系统性增加对 免疫系统导致慢性Th2免疫反应的发展和IL-10增强。 重要的是，将在Th1条件下发育的CD4 T细胞朝着Th2驱动（IL-4，IL-13，IL-10） 在DKK-1的存在下表型。我们提出了两个目标，以检查血小板/dkk-1之间的相互作用 利什曼原虫主持人和适应性免疫反应的几个关键点。在第一个目标中， 将解决DKK-1从血小板中释放的机制。由于激活取决于TLR2， 将使用缺乏表征表面毒力因子的Leishmania突变体。鉴于已知 PMN白细胞（中性粒细胞）在利什曼原虫感染中的重要性，我们还将通过 DKK-1会增加白细胞 - 血压计聚集体（LPA），并将白细胞募集到感染部位。这 第二个目标将特异性探测LRP6 CD4 T细胞中条件缺失的后果， DKK-1和C-MAF的受体以及IL-10和LRP6受体的中性粒细胞缺失。目标是 研究这些因素在血小板，CD4 T细胞和中性粒细胞中的贡献 导致疾病的敏感性或无法引起无菌免疫力，从而导致持续感染。拍摄 这项建议将共同为理解寄生识别和 感染过程中的逃避和随之而来的发病机理。我们的建议主要关注调查 通过宿主病原体引发和维持过度效应免疫反应的机制 相互作用。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面作用，因此 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 相关的生物途径是利什曼病和潜在的其他感染性的有效治疗靶标 疾病。