Stefan Kappe’s laboratory is focused on the biology of malaria parasite mosquito stages and mammalian liver stages. The goal is to understand liver stage parasite metabolism and elucidate networks of host-parasite interactions during liver infection. We utilize this knowledge to develop new interventions. In addition, the development of whole organism, genetically engineered vaccines to prevent malaria infection is a major goal. Kappe received a prestigious Grand Challenges in Global Health grant from the Bill & Melinda Gates Foundation in 2005, targeted at designing genetically engineered, live attenuated Plasmodium falciparum vaccine strains.  Kappe's GAP vaccine strain is currently undergoing clinical testing.

Research

The Plasmodium sporozoite stage, which develops in mosquitoes, is transmitted by mosquito bite and initiates the infection of the mammalian host liver. Kappe's lab works with rodent models of malaria and with the human parasite Plasmodium falciparum. In-house insectaries allow the Kappe lab to model the complete life cycle of the malaria parasites. The Kappe lab has identified numerous proteins that are involved in the invasion process and others that are needed for the establishment of the parasites' intracellular niche and subsequent growth in the liver. The function of these proteins is elucidated using genetic, molecular biological and cell biological tools. The lab has shown that deletion of genes that encode sporozoite secretory proteins causes severe deficiencies in successful infection. Furthermore, depletion of proteins of the vacuolar compartment surrounding the intra-hepatic liver stage results in a severe defect in liver stage development. Vacuolar proteins mediate critical liver stage-hepatocyte interactions. Kappe has also conducted work on endogenous lipid synthesis of Plasmodium and demonstrated that the parasite completely depends on this pathway only during late liver stage development and exo-erythrocytic merozoite formation. The lab is also conducting systems biology studies to identify host responses to parasite liver infection.

Immunizations with genetically-attenuated parasites developed in the Kappe ab confer complete protection against virulent parasite infection in mouse models of malaria. Using this model, the Kappe lab collaborates with the Wang and Crispe laboratories to elucidate immune mechanisms of protection, identify biomarkers of protection and find new potential liver stage subunit vaccine candidates.

Themes

• Molecular motor that powers malaria parasite motility and invasion
• Gene expression in the malaria sporozoite and liver stage
• Virulence factors mediating productive sporozoite-hepatocyte interactions
• Liver stage-hepatocyte interactions
• Liver stage vaccine development
• Liver stage metabolism

The National Institutes of Health (NIH), the Bill & Melinda Gates Foundation and the Medicines for Malaria Venture provide support for Kappe's current research.