The Multifactorial Roles of Platelets in Uncomplicated Malaria Infection

血小板在单纯性疟疾感染中的多因素作用

• 批准号: 10313019
• 负责人: Sara Katharina Blick-Nitko
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10313019
• 关键词: Achievement; Address; Anti-malarial drug resistance; Basic Science; Biochemical Pathway; Biochemistry; Biology; Blood; Blood Platelets; Cells; Clinical Sciences; Communicable Diseases; Complex; Complication; Disease; Disease Outcome; Economic Burden; Environment; Enzyme-Linked Immunosorbent Assay; Enzymes; Equilibrium; Faculty; Flow Cytometry; Gene Expression; Goals; Hematological Disease; Host Defense; Human; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immunology; Infection; Interferon Type II; Kynurenine; Lead; Life; Malaria; Mediating; Mediator of activation protein; Mentors; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Modeling; Morbidity - disease rate; Mus; Parasites; Pathogenesis; Pathology; Pathway interactions; Plasmodium; Plasmodium vivax; Plasmodium yoelii; Platelet Count measurement; Public Health; Regulation; Research; Research Personnel; Research Proposals; Resources; Role; Source; Testing; Therapeutic; Thrombocytopenia; Thrombosis; Training; Tryptophan; Tryptophan 2,3 Dioxygenase; Tryptophan Metabolism Pathway; Universities; Vascular Diseases; Western Blotting; Work; career development; economic cost; effective therapy; first responder; global health; human data; immune function; immunoregulation; improved; in vivo; liquid chromatography mass spectrometry; malaria infection; member; metabolomics; mortality; novel; pathogen; research and development; response; transcriptome sequencing; vaccine development

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.

项目总结/摘要 疟疾引起的疟原虫寄生虫仍然是一个主要的公共卫生威胁，至少有2.3亿人 全球年度病例。间日疟原虫（Plasmodium vivax，P vivax）是单纯性疟疾（uncomplicated malaria，UCM）的病因， 通常不是致命的，但却是全球发病率和经济成本的主要原因。尽管付出了巨大努力，疫苗 发展已被证明是具有挑战性的，由于对抗疟疾药物的耐药性不断增加，并发症也 坚持。虽然血小板是血栓形成的细胞介质，但血小板也是最多的免疫调节剂。 血液中的细胞，以及对感染的第一反应者。血小板减少症是疟疾的常见并发症， 血小板计数的减少是疾病结果的负预测因子。疟疾感染是一种强烈的 干扰素γ（IFN γ）应答。IFN γ是吲哚胺2，3-双加氧酶（IDO 1）的强效诱导剂， 催化犬尿氨酸（Kyn）途径中色氨酸（Trp）代谢第一步的限制酶。 在疟疾感染中，Trp代谢可能会改变，作为调节免疫代谢反应的一种手段， 机制仍然未知。我们的血小板RNA测序数据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Trp代谢相关的基因表达增加，包括 IDO 1.此外，血小板在代谢途径调节中的作用通常很少被探索， 特别是在传染病中。PI引入了血小板参与免疫代谢的新观点 感染PI已经组建了一个具有血小板和免疫学互补专业知识的指导团队 （C Morrell; primary，M Rondina），传染病（C Morrell，M Rondina，L Steiner）和代谢组学（J Munger，M Rondina）指导她的研究和职业发展（所有成员）。处的环境 罗切斯特大学资源丰富，师资力量雄厚，并以在以下方面的研究成果而闻名： 传染病、血小板生物学和免疫学。使用互补的实验方法，如 液相色谱-质谱法、ELISA、PCR、蛋白质印迹和流式细胞术，PI将检测 假设血小板是UCM疟疾中IDO 1的来源，血小板减少导致IDO 1耗竭 和免疫失调PI将确定血小板在Trp代谢途径调节中的作用（目的 1)并探索血小板调节的疟疾感染免疫反应是否部分依赖于 色氨酸代谢途径（目的2）。进一步了解血小板和生化途径之间的相互作用 可以提供对血小板减少症在疟疾以外疾病中的影响的理解， 改善疟疾感染反应的方法以及改善许多人的血小板衍生疗法， 血液、代谢和免疫疾病。这项研究计划包含了新奇，可以开辟新的 在免疫学，病理学和生物化学领域的综合研究的途径，在临床和 基础科学水平。完成PI中所述的辅导活动和职业发展 培训计划将有助于PI成为独立研究员的长期目标。