Development and function of CD4+ memory T cells during malaria

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Noah Sullivan Butler
Organization: UNIVERSITY OF IOWA
Fiscal Year: 2024
Award: $466,500
Funding agency: National Institute of Allergy and Infectious Diseases

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.

Terms: <Address><Affect><Agonist><Anti-malarials><Antibody Response><Antigen-Presenting Cells><Applied Genetics><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Biology><Blood><Blood Reticuloendothelial System><Blood erythrocyte><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Characteristics><Communicable Diseases><Contracting Opportunities><Contracts><DNA><Data><Death><Defect><Deoxyribonucleic Acid><Deposit><Deposition><Development><Disease><Disorder><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Erythrocytes><Erythrocytic><Exhibits><Family><Family member><Genetic><Gln><Glutamine><Goals><Groups at risk><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hemoglobin><Immune><Immune mediated therapy><Immune memory><Immune response><Immunes><Immunity><Immunologic Memory><Immunological Memory><Immunological response><Immunologically Directed Therapy><Immunology><Immunotherapy><Impairment><Individual><Inducer Cells><Inducer T-Lymphocytes><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammasome><Inflammation><Innate Immunity><Intermediary Metabolism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Journals><Knowledge><L-Glutamine><Link><Magazine><Maintenance><Malaria><Marrow erythrocyte><Mediating><Medicine><Memory><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Molecular><Molecular Genetics><Murine><Mus><Native Immunity><Natural Immunity><Nature><Non-Specific Immunity><Nonspecific Immunity><Paludism><Parasite Control><Parasites><Parasitology><Pathogenesis><People at risk><Persons at risk><Phenotype><Plasmablast><Plasmodium><Plasmodium Infections><Population><Populations at Risk><Predisposition><Publications><Q Levoglutamide><Q. Levoglutamide><Reagent><Red Blood Cells><Red Cell><Regulation><Reporting><Research><Resistance><Resolution><Scientific Publication><Severity of illness><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Subcellular Process><Susceptibility><Symptoms><System><T cell differentiation><T cell response><T-Cell Development><T-Cell Ontogeny><T-Cell Subsets><T-Lymphocyte Development><T-Lymphocyte Subsets><T4 Cells><T4 Lymphocytes><Testing><Vaccines><accessory cell><adaptive immunity><anamnestic reaction><anti-malarial agents><anti-malarial drugs><beta-hematin><biological signal transduction><blood corpuscles><burden of disease><burden of illness><cofactor><cytokine><deprivation><developmental><disease burden><disease severity><drinking water><epigenetically><genetic approach><genetic strategy><global health emergency><haemozoin><hemozoin><host response><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunoresponse><improved><innovate><innovation><innovative><insight><interventional strategy><malaria pigment><memory CD4 T cell><memory CD4 T lymphocyte><new approaches><novel><novel approaches><novel strategies><novel strategy><pathogen><programs><resistant><resolutions><response><secondary immune response><tool>