Stefan Kappe’s laboratory is focused on the biology of the malaria parasite pre-erythrocytic stages: the mosquito stage and the mammalian liver stage. The goal of the lab is to understand liver stage parasite development and elucidate networks of host-parasite interactions during liver stage infection. We utilize this knowledge to develop new interventions, both drugs and vaccines. Dr. Kappe received a prestigious Grand Challenges in Global Health grant from the Bill & Melinda Gates Foundation in 2005, which is targeted at designing genetically engineered, live attenuated Plasmodium falciparum vaccine strains. Dr. Kappe's genetically attenuated parasite (GAP) vaccine strain is currently undergoing clinical testing.
The Plasmodium sporozoite stage is transmitted by mosquito bite and initiates the infection of the mammalian host by invading liver cells, within which the parasite continues to develop as a liver stage. This liver stage ultimately spawns tens of thousands of new parasite forms that infect red blood cells and initiate the pathogenic blood stage cycle. Few parasites infect the liver, so accordingly, the liver stage constitutes an Achilles’ heel. By effectively eliminating liver stages, we can completely prevent malaria infection.
The parasite’s interaction with its host cell, the hepatocyte, is a central focus of our laboratory. We have identified numerous parasite proteins that mediate sporozoite invasion of hepatocytes and other proteins that are needed to establish and maintain liver stage development. The function of these proteins is elucidated using genetic, molecular biological, and cell biological tools. Gene deletions that eliminate essential parasite infection-factors cause severe deficiencies in liver stage development. Furthermore, we are interested in delineating the parasite-host cell interaction network on the molecular and cellular level. This has already led to the identification of host factors that are critical for parasite liver infection. We are also studying unique metabolic properties of the liver stage that can be exploited for intervention.
Our discovery of essential parasite factors for hepatocyte infection and development of liver stages provided us with an amazing tool: the genetically attenuated parasite (GAP). These GAPs ignited a new field that spans parasite biology, immunology, and vaccine development. Immunizations with GAPs confer complete protection against parasite infection in mouse models of malaria. We are developing GAPs for human vaccination. Using the GAP model, we collaborate with the Wang and Crispe laboratories at Seattle BioMed as well as the Harty laboratory at the University of Iowa to elucidate immune mechanisms of protection, identify biomarkers of protection, and find new potential liver stage subunit vaccine candidates.
- Gene expression, post-transcriptional regulation and protein expression in the malaria sporozoite and liver stage
- Virulence factors mediating productive sporozoite-hepatocyte interactions
- Liver stage-hepatocyte interactions
- Host factors for infection
- Pre-erythrocytic vaccine development
- Pre-erythrocytic immunity
- Liver stage metabolism
- Humanized mouse model of liver stage development
The National Institutes of Health (NIH), the Bill & Melinda Gates Foundation, the Department of Defense (DoD), private donors, and the Malaria Vaccine Initiative arm of PATH fund Dr. Kappe’s research.