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Development and function of CD4+ memory T cells during malaria

疟疾期间 CD4 记忆 T 细胞的发育和功能

基本信息

批准号：
9157297
负责人：
Noah Sullivan Butler
金额：
$ 32.65万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
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：
2016-06-15 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9157297
关键词：
Acute Address Adoptive Transfer Antibodies Antibody Response Antibody-mediated protection Antigens Biochemical Biology Blood CD4 Positive T Lymphocytes Cell Count Cells Chronic Clinical Clinical Trials Communicable Diseases Comparative Study Contracts Data Development Disease Emergency Situation Erythrocytes Genetic Goals Growth Helper-Inducer T-Lymphocyte Human Humoral Immunities Immune Immunity Immunologics Immunotherapeutic agent Infection Inflammation Interferon Type II Intervention Lead Life Maintenance Malaria Measures Mediating Memory Methods Modeling Molecular Profiling Mus Parasite Control Parasites Pathogenesis Pathway interactions Phenotype Plasmodium Population Positioning Attribute Publishing Research Resistance Resolution Risk Severity of illness Signal Transduction Staging Symptoms T cell response T-Lymphocyte T-Lymphocyte Epitopes T-Lymphocyte Subsets Testing Tissues Transgenic Mice Vaccination Vaccines Virus Diseases Work base burden of illness cytokine global health immunopathology improved innovation insight memory CD4 T lymphocyte novel novel strategies pathogen research study

项目摘要

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 this is due to deficient Plasmodium-specific effector and memory CD4+ T cell formation. One of the most critical challenges to developing new immune-based therapies or vaccines against Plasmodium is understanding how or whether long-lived Plasmodium-specific memory CD4+ T cells develop, function and persist following infection. In this project we have developed powerful new cellular, genetic and biochemical approaches that enable direct, high-resolution analyses of bona fide Plasmodium-specific memory CD4+ T cells. These new approaches facilitate our long-term goal to understand the quantity and quality of Plasmodium-specific memory CD4+ T cell responses. Our goal is addressed by three specific aims that test: 1) the phenotype, function and numerical stability of Plasmodium-specific effector and memory CD4+ T cell populations and their impact on protective humoral immunity; 2) how parasite- and host-specific factors regulate the formation of long-lived memory CD4+ T cell responses; and 3) the effector mechanisms and pathways that memory CD4+ T cells use to orchestrate long-lived anti-Plasmodium immunity. Our innovative approaches enable us to establish additional new paradigms for understanding and enhancing CD4+ T cell-dependent anti-Plasmodium immunity. Understanding immune memory formation following Plasmodium infection will enable us to identify and develop new immune-based strategies to limit Plasmodium pathogenesis and disease burden.

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。我们假设这是由于疟原虫特异性效应器和记忆缺陷造成的 CD4+ T 细胞形成。开发新的免疫疗法或药物面临的最关键挑战之一疟原虫疫苗正在了解如何或是否能够长期维持疟原虫特异性记忆 CD4+ T 细胞在感染后发育、发挥作用并持续存在。在这个项目中我们开发了强大的新产品细胞、遗传和生化方法，可对真实的结果进行直接、高分辨率的分析疟原虫特异性记忆 CD4+ T 细胞。这些新方法有助于我们的长期目标疟原虫特异性记忆 CD4+ T 细胞反应的数量和质量。我们的目标是通过测试的三个具体目标：1）疟原虫特异性效应子的表型、功能和数值稳定性和记忆 CD4+ T 细胞群及其对保护性体液免疫的影响； 2）如何寄生 - 和宿主特异性因子调节长寿命记忆 CD4+ T 细胞反应的形成； 3）效应器记忆 CD4+ T 细胞用于协调长期抗疟原虫免疫的机制和途径。我们的创新方法使我们能够建立更多新的范例来理解和增强 CD4+ T 细胞依赖性抗疟原虫免疫。了解以下免疫记忆形成疟原虫感染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发病机制和疾病负担。