Malaria, caused by Plasmodium parasites and transmitted via mosquito bite, caused over 600,000 deaths in 2022, making the disease a pertinent public health problem. After injection into mammalian hosts through mosquito bite, Plasmodium parasites travel into the liver and develop in hepatocytes, where they undergo massive replication but cause no symptomatic disease. The parasites then egress into the bloodstream, where they infect red blood cells and cause the clinical symptoms and mortality associated with malaria, along with transmission to mosquitos to continue the cycle of infection. Although the liver-stage of the parasite is clinically silent, parasite infection of the liver results in incompletely understood hepatic immune responses that impact the development of immune memory, which is necessary for protection from future infections. Innate-like αβ and γδ T cells make up a significant proportion of intrahepatic lymphocytes, leading us to become interested in how these immune cells respond to a primary Plasmodium parasite infection of the liver. To address the role of these T cells in combating a primary liver-stage infection, we infected wildtype mice, mice that lack αβ T cells, and mice that lack γδ T cells with Plasmodium parasites and examined parasite density, size, and hepatic localization using immunofluorescence microscopy. Preliminary results demonstrate no significant differences in malaria parasite susceptibility between wildtype mice, mice without αβ T cells, and mice without γδ T cells, indicating that these cell types alone may not mount a significant anti-Plasmodium response upon primary infection. Future work will involve examining T cell localization within infected tissues to determine how T cell localization is impacted by primary infection and characterizing subsets of T cells that are present in infected livers. We hope these results add to a greater understanding of the entire hepatic immune response to primary Plasmodium parasite infection of the liver.

Malaria, caused by Plasmodium parasites, infects millions of people across the globe and leads to over half a million deaths annually. Infection begins when a mosquito takes an infectious blood meal, resulting in the deposition of infectious parasites known as sporozoites into the skin. Sporozoites traffic from the skin into the liver and undergo clinically silent development in hepatocytes.  This liver stage development is required for the transition into blood stage development where all the clinical symptoms of malaria and transmission back into mosquito vectors occur. No highly efficacious malaria vaccines exist, but one promising vaccination strategy is immunization with sporozoites that are impaired in their ability to complete liver stage development.  These attenuated whole parasite vaccines provide robust immune protection in malaria-naive individuals, but further refinement of this approach is required before this strategy can be deployed globally in endemic regions.  We have shown that the type 1 interferon (IFN-1) signaling regulates the immune response induced by whole parasite vaccines. My project aims to spatially characterize how IFN-1 influences parasite development within the liver using immunofluorescence. Interferon-alpha/beta receptor knockout (Ifnar-) mice (which are impaired for IFN-1 signaling) and wildtype C57Bl/6 mice were infected with Plasmodium yoelli. We then harvested livers from infected mice at various time points during liver stage development. I observed that IFN-1 restricts parasite development beginning at 24 hours post-infection but does not impact parasite size in hepatocytes. Future studies will selectively eliminate IFNAR on hepatocytes or on distinct immune cells to identify if IFN-1 mediated parasite restriction is hepatocyte intrinsic or is immune cell mediated.