Plasmodium infections and the disease malaria remain global health emergencies. Malaria affected more than200 million people last year, killing nearly 600,000. Antibody responses that target the parasite are essential forcontrolling parasite replication and limiting the severity of malaria. Potent antibody responses and optimallystimulated B cells require `help' from CD4+ T cells. Our published work has shown that CD4+ T cell function ismarkedly impaired following Plasmodium infection. We linked the reduced function of CD4+ T cells to theinduction of co-inhibitory receptor expression, a class of T cell surface expressed proteins that directly limit theability of CD4+ T cells to orchestrate protective immune responses against microbial pathogens. We furthershowed that blocking the activity of co-inhibitory receptors during malaria restored CD4+ T cell function,promoted strong antibody responses and accelerated parasite control and clearance from the infected host. Recently, we identified that we can also restore the function of Plasmodium-specific CD4+ T cells byactivating OX40, a member of a class of T cell stimulating receptors. Our new data show that therapeuticallystimulating the OX40 receptor during the second week of experimental Plasmodium infection overcomes co-inhibitory networks, markedly improves CD4+ T cell activity and secreted antibody responses, and limitsmalaria parasite replication. Importantly, we also identified parallels in children infected with P. falciparum,establishing the relevance and significance of our discoveries and strengthening the scientific premise of thecurrent proposal. In this project we apply new cellular, genetic and parasitological reagents to study how theOX40 receptor regulates communication between parasite specific CD4+ T cells and B cells and thegeneration of antibody responses. Our scientific questions and experimental approaches facilitate our long-term goal to identify new immune-based approaches to therapeutically stimulate host resistance againstmalaria. Our goal is addressed by three specific aims that will determine: 1) the distinct characteristics ofPlasmodium infection that uniquely regulate the functional expression of OX40 receptors on CD4+ T cells; 2)whether the OX40 receptor is required for effective communication between CD4+ T cells and B cells togenerate potent antibody responses; and 3) whether B cell expression of the OX40 ligand is regulated byparasite byproducts and necessary for generating potent secreted antibody responses. Our proposed studiesand new reagents provide tractable systems and a detailed framework for sustainable extensions of thisproject that will establish additional new paradigms for enhancing CD4+ T cell-mediated immunity againstPlasmodium. Insight gained during the course of our studies will help us identify and develop new immune-based strategies to limit Plasmodium 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 our research is to identify anddevelop new immune-based interventions that improve the function of cells that are critical for resistance toblood stage Plasmodium infection. These studies will enable us to enhance immunity against malaria.
