Exploring the role of Plasmodium circumsporozoite-specific ZEB2+ cytolytic effector memory CD4+ T cells in protection against malaria 3804

Description Malaria remains a major global health threat, causing about 247 million cases and half a million deaths annually. The two WHO-approved vaccines (RTS,S/AS01 and R21/Matrix-M) both target the circumsporozoite protein (CSP) antigen of the Plasmodium falciparum parasite. However, the vaccines have limited efficacy in preventing clinical malaria, and their protection wanes over time. While circulating anti-CSP antibodies are known to contribute to natural and vaccine-induced immunity, the cellular immune correlates of protection are less well understood. In a prospective cohort study in a malaria-endemic region of Malawi, we used single cell sequencing, high dimensional flow cytometry, and functional assays to discover a clonally expanded, CSP-specific, cytolytic memory CD4+ T cell population among clinically immune individuals. We hypothesize that these effector memory CD4+ T cells may be key contributors to protection against liver stage infection. By generating Jurkat reporter lines expressing the TCRs of expanded clones and patient autologous EBV immortalized B cell lines, we are defining which CSP epitopes ZEB2+ CD4+ T cells react to. Using radiation-attenuated sporozoite immunization in ZEB2 reporter and loss-of-function mouse models, we are investigating if ZEB2+ CD4+ T cells differentiate, establish liver residency, and protect against live infection. Taken together, we will be discussing whether ZEB2+ CD4+ T cells may represent new correlates of protection in malaria. Funding Sources T32TR004537 Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)