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Here, in unpublished preliminary data, we provide evidence that Tcircm can indeed provide protective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