Saturday, May 17, 2025
5/17/2025
Immunity to Liver-stage malaria - Malaria, caused by Plasmodium species, is an unresolved global health burden. Although insecticide treated bed nets and antimalarial drugs have reduced the incidence and severity of malaria in some regions, >200,000,000 cases still occur annually with >400,000 fatalities, most of which occur in young children in sub-Saharan Africa. Thus, effective vaccines remain an as yet unrealized but critical goal to combat the global threat of malaria. However, development of potent and translatable vaccines against malaria has been hampered by our incomplete understanding of the mechanisms by which the immune system can be trained to control Plasmodium infections. We have been studying CD8 T cell immunity to liver-stage (LS) malaria for ~13 years. During this time, we studied immunity against whole parasite immunizations (RAS and late-arresting GAP) and studied epitope-specific prime-boost immunization strategies that were capable of generating sterilizing immunity to sporozoite challenge in mice. A major finding from the latter studies was that sterilizing immunity occurred when the immunization generated circulating malaria-specific memory CD8 T cells (hereon called Tcircm) that exceeded a large, but definable frequency. We also showed that large numbers of epitope-specific CD8 T cells were present in the livers of immunized mice. In contrast, studies from our group and others showed that sterilizing RAS immunization generated relatively small Tcircm responses, although these responses were enriched in the liver. This apparent conundrum was recently explained by the discovery that RAS immunization generates a very potent liver CD8 T resident memory population (from here, called liver Trm) that is essential for sterilizing immunity in this vaccination model. Trm, occupy many tissues and play important roles in tissue specific immunity. These findings have galvanized the malaria field to focus on novel immunization strategies to generate Trm to improve LS vaccines. While the importance of liver Trm in RAS vaccine induced protection from Plasmodium cannot be overstated, it remains unclear to what degree, if any, Tcircm contribute to protection against LS infection. Here, in unpublished preliminary data, we provide evidence that Tcircm can indeed provide protective immunity against LS Plasmodium infection using an as yet undefined mechanism for rapid recruitment to the liver. The long-term goals of this proposal are to dissect mechanisms leading to generation and function of memory CD8 T cells that can provide potent immunity to Plasmodium LS infection in order to inform development of human vaccines. We will address these goals with the following Specific Aims: SA 1. Determine the mechanisms underlying rapid recruitment of Tcircm to the liver SA 2. Dissect the mechanisms of liver-stage protection by Tcircm SA 3. Determine if and how Tcircm cooperate with Trm in control of liver-stage malaria
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