Impaired trafficking and transfer of virulence factors to the surface of P. falciparum-infected erythrocytes containing the hemoglobin polymorphisms HbS and HbC

• Antragsteller: Professor Dr. Michael Lanzer
• Fachliche Zuordnung: Evolution, Anthropologie
• Förderung: Förderung von 2009 bis 2013
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 130261016

It has long been appreciated that certain erythrocyte polymorphisms, such as hemoglobin S (HbS) and hemoglobin C (HbC), protect against severe malaria. Recent developments have now suggested that these hemoglobinopathies have emerged under the selective pressure to escape severe disease and death resulting from the cytoadhesion of P. falciparum-infected erythrocytes in the microvasculature. Parasitized erythrocytes containing HbS and HbC exhibit an impaired cytoadhesive phenotype that correlates with an altered display and a reduced amount of the disease-mediating adhesin PfEMP1 on the erythrocyte surface, as compared to normal erythrocytes of the hemoglobin A type. To explain this altered phenotype, we hypothesize that export and transfer of the adhesin to the surface of the host erythrocyte is impaired in HbS and HbC containing erythrocytes. We will investigate our working hypothesis by studying, in HbS and HbC erythrocytes, the protein export pathway, including the time frame of export, the development of the Maurer’s clefts and the anchoring of these membrane profiles and the cytoadhesion complex to the erythrocyte membrane skeleton. Our approach will include cryo-electron tomography, fluorescence microscopy of GFP-tagged exported proteins, a conditional protein export system to monitor protein export in real time, and a biochemical approach to study the interactions of the Maurer’s clefts and the cytadhesion complex with the erythrocyte membrane skeleton.

• DFG-Verfahren: Schwerpunktprogramme
• Teilprojekt zu: SPP 1399: Host-Parasite Coevolution - Rapid Reciprocal Adaptation and its Genetic Basis
• Beteiligte Person: Dr. Marek Cyrklaff