Malaria, caused by parasites belonging to the genus Plasmodium, accounts for roughly 600,000 deaths per year, with the most vulnerable population being children under 5 years old. The current available malaria vaccines show limited effectiveness in children. After being deposited by the bite of an infected mosquito, Plasmodium travels through the bloodstream and invades liver hepatocytes, causing an asymptomatic infection. Within hepatocytes, Plasmodium multiplies until the hepatocyte bursts, in which they are released into the bloodstream to cause a symptomatic infection. To develop an effective vaccine for children, it is critical to understand the immune response to liver stage Plasmodium infection in children. However, our current understanding of immune responses in children compared to adults, specifically in the liver, is limited. During Plasmodium infection, CD8 T cells in the liver are able to confer sterilizing protection. The main goal of this study is to identify differences in the spatial location of immune cells in human liver tissue across ages. We are currently utilizing a combination of RNAscope and immunofluorescent assay (IFA) staining to visualize CD8αα+ T cells expressing the promyelocytic leukemia zinc finger (PLZF) transcription factor, which distinguish them from conventional CD8+ memory-like cells as innate-like T cells. These unconventional cells play a key role in autoimmune responses in the liver. We are doing further spatial analysis on Imaris to gather quantitative data on these samples. We hypothesize that children would express higher levels of CD8αα+ T cells expressing PLZF because they do not produce memory-like cells as well as adults, and thus lack an efficient response to infections. The results of this study will help us better understand the differences that age may cause in immune cell types and quantities, and how this can be used to develop a more effective malaria vaccine for children.

Malaria, a disease caused by the Plasmodium parasite, kills approximately 600,000 people per year. This disease consists of two stages, first an asymptomatic liver stage, followed by a symptomatic blood stage. The goal of our lab is to eliminate the transmission and spread of the parasite via the use of genetically modified parasites as vaccines. These parasites die in the liver, preventing blood infection and creating long-term immunity in the liver. Previous research in our group has shown that our vaccine model is effective in mice, with improved efficacy when the type-1 interferon response to the vaccine is disabled. Type-1 interferons are cytokines produced in an early immune response to a variety of pathogens. Yet, the mechanism in which these interferons are activated in a Plasmodium-infected liver cell is unknown. My project's goal is to identify and understand the mechanism in which this early immune response is turned on in response to parasite infection. To do this, I am developing an in-vitro system which can quantify the type-1 interferon response in Plasmodium-infected liver cells in culture. Utilizing various in-vitro techniques, we can identify the sensors, adaptors, and transcription factors that are most important in upregulating this early immune response. This knowledge will be used to inform methods to inactivate the type-1 interferon response, in turn improving our vaccine model. Our lab hopes to eventually use our model in humans for the goal of eradicating malaria from the modern world.