Regulation of Plasmodium-specific CD4+ T cells

疟原虫特异性 CD4 T 细胞的调节

基本信息

批准号：
10676649
负责人：
Noah Sullivan Butler
金额：
$ 46.65万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-26 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676649
关键词：
Acute Address Agonist Amino Acid Transporter Antibody Response Antigen-Presenting Cells Antimalarials Applied Genetics B-Lymphocytes Biological Biology Blood CD4 Positive T Lymphocytes Cell Compartmentation Cell physiology Cells Cessation of life Communicable Diseases Contracts Data Deposition Development Disease Erythrocytes Event Failure Gene Expression Profile Genetic Transcription Glutamine Goals Helper-Inducer T-Lymphocyte Hemoglobin Humoral Immunities Hypoxia Immune Immune response Immunity Immunology Immunotherapy Individual Infection Inflammasome Inflammation Intervention Journals Knowledge Link Malaria Mediating Medicine Metabolic Metabolism Molecular Molecular Genetics Mus Natural Immunity Nature Parasite Control Parasites Parasitology Pathogenesis Pathway interactions Physiological Plasmablast Plasmodium Population Populations at Risk Predisposition Publications Publishing Reagent Regulation Reporting Research Resistance Resolution Severity of illness Signal Transduction Symptoms System T cell differentiation T cell response T-Cell Development T-Lymphocyte Subsets Testing Vaccines adaptive immunity burden of illness cell mediated immune response drinking water functional improvement genetic approach global health emergency hemozoin immunoregulation innovation new therapeutic target novel novel strategies pathogen programs response transcriptomics

项目摘要

PROJECT SUMMARY Plasmodium infections and the disease malaria remain global health emergencies. Plasmodium parasites replicate within and cause the destruction of host red blood cells, which triggers inflammation and causes the symptoms of malarial disease. Parasite-specific antibody responses that develop following infection are critical for controlling parasite burden and limiting disease severity. CD4+ helper T cells are essential for coordinating these protective antibody responses. However, sterilizing anti-Plasmodium immunity rarely develops, even following repeated infection. We hypothesize immune failures are mechanistically linked to aberrant or inefficient Plasmodium-specific effector CD4+ T cell development and function. One of the most critical challenges to developing new immune-based therapies or vaccines against Plasmodium is understanding the mechanisms by which Plasmodium-specific CD4+ T cells develop, function and regulate humoral immunity following infection. In the continuation of this project, we apply powerful new cellular and molecular genetic approaches that enable direct, high-resolution analyses of Plasmodium-specific CD4+ T cells. These new approaches facilitate our long-term goal to understand the mechanisms governing the development and function of Plasmodium- specific CD4+ T cell responses. Our goal is addressed by two specific aims that have evolved to test: 1) how parasite-derived molecules influence cell antigen presenting functions and priming of Plasmodium-specific CD4+ T populations; and 2) how host physiological perturbations and constraints on cellular metabolism regulate CD4+ T cell development and function. Our innovative conceptual and technical advances and mechanistic approaches enable us to establish additional new paradigms for understanding and enhancing CD4+ T cell-dependent anti- Plasmodium immunity. Understanding cellular and molecular events governing CD4 T+ T cell responses during malaria will enable us to identify and develop new immune-based strategies to limit Plasmodium pathogenesis and disease burden.

项目概要疟原虫感染和疟疾仍然是全球卫生紧急情况。疟原虫寄生虫在宿主红细胞内复制并导致宿主红细胞破坏，从而引发炎症并导致疟疾疾病的症状。感染后产生的寄生虫特异性抗体反应至关重要用于控制寄生虫负担和限制疾病严重程度。 CD4+ 辅助 T 细胞对于协调至关重要这些保护性抗体反应。然而，杀菌抗疟原虫免疫力很少发展，即使反复感染后。我们假设免疫失败在机制上与异常或低效有关疟原虫特异性效应 CD4+ T 细胞的发育和功能。最严峻的挑战之一开发新的针对疟原虫的免疫疗法或疫苗正在了解其机制疟原虫特异性 CD4+ T 细胞在感染后发育、发挥作用并调节体液免疫。在该项目的延续中，我们应用了强大的新细胞和分子遗传学方法，能够对疟原虫特异性 CD4+ T 细胞进行直接、高分辨率的分析。这些新方法有利于我们的长期目标是了解控制疟原虫发育和功能的机制- 特异性 CD4+ T 细胞反应。我们的目标是通过两个具体目标来实现的，这些目标已经发展到测试：1）如何寄生虫衍生分子影响细胞抗原呈递功能和疟原虫特异性 CD4+ 的启动 T 人群； 2) 宿主生理扰动和细胞代谢限制如何调节 CD4+ T 细胞的发育和功能。我们的创新概念和技术进步以及机械方法使我们能够建立额外的新范例来理解和增强 CD4+ T 细胞依赖性抗- 疟原虫免疫力。了解控制 CD4 T+ T 细胞反应的细胞和分子事件疟疾将使我们能够识别和开发新的基于免疫的策略来限制疟原虫的发病机制和疾病负担。