(For the funded R01 GM118553 proposal). Malaria, a disease caused by parasites of Plasmodium species, re- mains one of the most relevant infectious diseases; in 2015 over 200 millions of individuals had clinical malaria and over 500,000 individuals, mainly children, died from it. The infection starts when a Plasmodium-infected mosquito injects into the skin a small dose of sporozoites, a speci?c form of the parasite, which travel via the blood to the liver, infect hepatocytes, and form liver stages. Several vaccine candidates, including the most re- cent RTS,S vaccine, are aimed at eliminating sporozoites from the skin, blood, or hepatocytes. However, the low ef?cacy of such vaccines highlights the problem with lack of basic understanding of how Plasmodium sporozoites are eliminated by host immunity. CD8 T cells, a subset of lymphocytes, have been shown to play an important role in preventing clinical malaria by eliminating Plasmodium liver stages, speci?cally in radiation attenuated sporo- zoites (RAS)-based vaccines. Using intravital imaging, we have recently discovered that activated CD8 T cells form clusters around Plasmodium-infected hepatocytes in mice and that these clusters are important in parasite elimination. Mechanisms driving the formation of such clusters remain poorly de?ned and how activated CD8 T cells eliminate liver stages from the whole liver is not well understood. Another layer of complexity arises as the level of immunity needed for protection depends on a speci?c host-parasite combination. By combining math- ematical modeling and experiments we will provide quantitative insights into potential mechanisms that explain contribution of CD8 T cells to elimination of Plasmodium liver stages in mice. We will provide such insights via three complementary speci?c aims. In speci?c Aim 1, we will discriminate between alternative mechanisms of formation of CD8 T cell clusters around sporozoite-infected hepatocytes (T-cell intrinsic vs. T-cell extrinsic), de?ne the role of T cells, speci?c to irrelevant antigens, in the formation of clusters, and quantify the impact of T cell cluster size on the ef?ciency at which liver stages are eliminated. In speci?c Aim 2, we will determine the impact of structure of liver sinusoids on the ef?ciency of CD8 T search for rare sporozoite-infected hepatocytes and de- termine the speed at which moving CD8 T cells can localize the site of infection. Finally, in speci?c Aim 3 we will discriminate between alternative mechanisms for a larger number of memory CD8 T cells required for sterilizing protection against exposure to Plasmodium yoelii sporozoites as compared to Plasmodium berghei sporozoites. Completion of these aims will lead to a better understanding how CD8 T cells localize and eliminate Plasmodium liver stages from one of the major peripheral tissues, the liver. This understanding may help in designing more ef?cient immunization protocols of RAS-based malaria vaccines. In addition, deeper understanding of the mech- anisms by which CD8 T cells eliminate infections at peripheral sites may be also useful for the improvement of several others CD8 T cell-based vaccines such as those against HIV, HCV, and HSV.
Research Narrative A number of vaccine candidates against several viral and parasitic infections induce high levels of CD8 T cells whose aim is to locate and eliminate pathogen-infected cells. Yet, limited quantitative details are known how CD8 T cells actually perform their search for the site of infection, how they eliminate the pathogen, and how many CD8 T cells are needed to provide protection against an infection. Using a combination of mathematical modeling and experimental infections of mice with Plasmodium parasites we will determine how vaccine-induced CD8 T cells eliminate the Plasmodium liver stages.
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