The Multifactorial Roles of Platelets in Uncomplicated Malaria Infection

项目摘要/摘要 导致疟疾寄生虫的疟疾仍然是一个主要的公共卫生威胁，至少有2.3亿人 全球每年的病例。间日疟原虫(P间日疟原虫)是单纯疟疾(UCM)的病因，而 通常不是致命的，是造成重大全球发病率和经济损失的原因。尽管付出了巨大的努力，疫苗 发展已被证明具有挑战性，由于对抗疟疾药物的抗药性日益增长，并发症也 坚持不懈。虽然血小板是血栓形成的细胞介质，但它也是数量最多的免疫 血液中的细胞，以及对感染的第一反应。血小板减少症是疟疾的常见并发症， 而血小板数量的减少是疾病结局的负面预测因素。疟疾感染引发强烈的 干扰素应答。干扰素是吲哚胺2，3-双加氧酶(IDO_1)的有效诱导剂。 在犬尿氨酸(Kyn)途径中催化色氨酸(Trp)代谢第一步的限制性酶。 在疟疾感染中，色氨酸代谢可能会改变，作为调节免疫代谢反应的一种手段，但 机制仍不清楚。我们来自感染间日疟原虫的人和来自 感染约氏疟原虫的小鼠表现出与色氨酸代谢相关的基因表达增加，包括 IDO1.此外，总体上对血小板在代谢途径调节中的作用的研究还很少，但 尤其是在传染病方面。PI引入了一种新的概念，即血小板参与免疫代谢 与感染有关。PI组建了一支指导团队，在血小板和免疫学方面具有互补的专业知识 (C Morrell；初级，M Rondina)，传染病(C Morrell，M Rondina，L Steiner)和代谢组学(J 芒格，M Rondina)，指导她的研究和职业发展(所有成员)。中国的环境 罗切斯特大学在资源方面出类拔萃，拥有一支学院教师队伍，并以在以下方面的研究成就而闻名 传染病、血小板生物学和免疫学。使用互补的实验方法，如 液-质联用、酶联免疫吸附试验、聚合酶链式反应、免疫印迹和流式细胞仪等检测 假设血小板是UCM疟疾中IDO1的来源，而血小板减少会导致IDO1耗尽 和免疫失调。等电点将决定血小板在色氨酸代谢途径调节(AIM)中的作用 1)并探索血小板调节的疟疾感染免疫反应是否在一定程度上依赖于 色氨酸代谢途径(目标2)。进一步了解血小板和生化途径之间的相互作用 可提供对血小板减少对疟疾以外疾病的影响的了解，并提供 改善疟疾感染反应的手段以及许多人改进的血小板衍生疗法 血液学、新陈代谢和免疫疾病。这项研究提案包含的新颖性可能会打开新的 在临床和生物化学领域的免疫学、病理学和生化的综合研究途径 基础科学水平。完成PI中所述的指导活动和职业发展 培训计划将促进PI成为独立研究人员的长期目标。

Project Summary/Abstract The malaria causing Plasmodium parasite continues to be a major public health threat, with at least 230 million annual cases worldwide. Plasmodium vivax (P vivax) is the cause of uncomplicated malaria (UCM), which while typically not deadly, is the cause of significant global morbidity and economic cost. Despite great efforts, vaccine development has proven challenging and due to growing resistance to anti-malarial drugs, complications also persist. While platelets are the cellular mediators of thrombosis, platelets are also the most numerous immune cells in the blood, and a first responder to infections. Thrombocytopenia is a frequent complication of malaria, and a decrease in platelet count is a negative predictor of disease outcome. Malaria infection elicits a strong interferon gamma (IFN) response. IFN is a potent inducer of indoleamine 2,3-dioxygenase (IDO1) the rate- limiting enzyme that catalyzes the first step in Tryptophan (Trp) metabolism in the kynurenine (Kyn) pathway. Trp metabolism may be altered in malaria infection as a means to regulate immunometabolic responses, but the mechanisms remain unknown. Our platelet RNA-sequencing data from humans infected with P vivax and from mice infected with Plasmodium yoelii showed increased expression of genes related to Trp metabolism, including IDO1. Furthermore, the role for platelets in metabolic pathway regulation is poorly explored in general, but particularly in infectious diseases. The PI introduces a novel idea that platelets participate in immunometabolism to infection. The PI has assembled a mentoring team with complementary expertise in platelets and immunology (C Morrell; primary, M Rondina), infectious diseases (C Morrell, M Rondina, L Steiner) and metabolomics (J Munger, M Rondina) to guide her research and career development (all members). The environment at the University of Rochester excels in resources, has a collegial faculty, and is noted for research achievements in infectious diseases, platelet biology and immunology. Using complementary experimental approaches such as liquid chromatography-mass spectrometry, ELISA, PCR, western blot, and flow cytometry, the PI will test the hypothesis that platelets are a source of IDO1 in UCM malaria, and thrombocytopenia results in IDO1 depletion and immune dysregulation. The PI will determine the role of platelets in Trp metabolic pathway regulation (Aim 1) and explore whether platelet regulated immune responses to malaria infection are in part dependent on the Trp metabolic pathway (Aim 2). Further understanding this interplay between platelets and biochemical pathways may provide an understanding of the impact of thrombocytopenia in diseases beyond malaria, and provide a means to improve malaria infection responses as well as improved platelet-derived therapeutics in many hematological, metabolic, and immune diseases. The research proposal contains novelty that could open new avenues for integrative research in the fields of immunology, pathology, and biochemistry at both clinical and basic science levels. The completion of the mentored activities and career development as described in the PI’s training plan will facilitate the PI’s long-term goal of becoming an independent researcher.