Plasmodium infections and the disease malaria remain global health emergencies. Plasmodium parasitesreplicate within and cause the destruction of host red blood cells, which triggers inflammation and causes thesymptoms of malarial disease. Parasite-specific antibody responses that develop following infection are criticalfor controlling parasite burden and limiting disease severity. CD4+ helper T cells are essential for coordinatingthese protective antibody responses. However, sterilizing anti-Plasmodium immunity rarely develops, evenfollowing repeated infection. We hypothesize this is due to deficient Plasmodium-specific effector and memoryCD4+ T cell formation. One of the most critical challenges to developing new immune-based therapies orvaccines 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 newcellular, genetic and biochemical approaches that enable direct, high-resolution analyses of bona fidePlasmodium-specific memory CD4+ T cells. These new approaches facilitate our long-term goal to understandthe quantity and quality of Plasmodium-specific memory CD4+ T cell responses. Our goal is addressed bythree specific aims that test: 1) the phenotype, function and numerical stability of Plasmodium-specific effectorand memory CD4+ T cell populations and their impact on protective humoral immunity; 2) how parasite- andhost-specific factors regulate the formation of long-lived memory CD4+ T cell responses; and 3) the effectormechanisms 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 enhancingCD4+ T cell-dependent anti-Plasmodium immunity. Understanding immune memory formation followingPlasmodium infection will enable us to identify and develop new immune-based strategies to limit Plasmodiumpathogenesis and disease burden.
Plasmodium infections cause more than 200 million cases of malaria each year and more than 3.4 billionpeople are at risk for contracting this devastating infectious disease. The goal of this research is to understandthe differentiation; function and maintenance of parasite-specific memory CD4 T cells that are critical forresistance to blood stage Plasmodium infection. These studies will provide new insight that will be used todevelop and enhance immune-based interventions against malaria.
