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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：
10604910
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：
2016-06-15 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604910
关键词：
Address Affect Agonist Antibody Response Antigen-Presenting Cells Antimalarials Applied Genetics B-Lymphocytes Biology Blood CD4 Positive T Lymphocytes Cell physiology Cells Cessation of life Characteristics Communicable Diseases Contracts DNA Data Defect Deposition Development Disease Enzymes Epigenetic Process Erythrocytes Exhibits Family Family member Genetic Glutamine Goals Helper-Inducer T-Lymphocyte Hemoglobin Immune Immune response Immunity Immunologic Memory Immunology Immunotherapy Impairment Individual Infection Inflammasome Inflammation Intervention Journals Knowledge Link Maintenance Malaria Mediating Medicine Memory Metabolic Metabolism Molecular Molecular Genetics Mus Natural Immunity Nature Parasite Control Parasites Parasitology Pathogenesis Phenotype Plasmablast Plasmodium Population Populations at Risk Predisposition Publications Reagent Regulation Reporting Research Resistance Resolution Severity of illness Shapes Signal Transduction Symptoms System T cell differentiation T cell response T-Cell Development T-Lymphocyte Subsets Testing Vaccines adaptive immunity burden of illness cofactor cytokine deprivation drinking water genetic approach global health emergency hemozoin improved innovation insight memory CD4 T lymphocyte novel novel strategies pathogen programs response tool

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 this is due to deficient Plasmodium-specific effector and memory 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 long-lived Plasmodium- specific memory CD4+ T cells develop, function and persist 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 memory CD4+ T cells. These new approaches facilitate our long-term goal to understand the mechanisms governing the development and function of Plasmodium-specific memory CD4+ T cell responses. Our goal is addressed by three specific aims that have evolved to test: 1) how hemozoin, a parasite-derived product of hemoglobin degradation, influences the induction and maintenance of Plasmodium-specific memory CD4+ T cell populations; 2) how constraints on host cellular metabolism shape memory CD4+ T cell formation and function; and 3) how specific epigenetic regulators govern the differentiation and function of CD4+ memory T cells. 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 immune memory formation following Plasmodium infection will enable us to identify and develop new immune-based strategies to limit Plasmodium pathogenesis and disease burden.

项目总结