BioMalPar

Main focus of our group is understanding the role of hemozoin (HZ) in P. falciparum malaria. Within this general theme we are focussing on following issues:

Study active components of HZ and their mechanism of action. HZ is a large crystalline aggregate of undigested heme from host hemoglobin, localized in the parasite’s food vacuole. It is avidly ingested by monocytes, leucocytes and macrophages and profoundly modifies several activities of those cells. According to isolation procedure, HZ may contain or not lipids, lipoperoxidation derivatives, proteins, parasitic DNA. Our golden standard is “native HZ”, ie HZ associated to intact food vacuoles, freshly shed after schizogony. We found that the poly-heme core is able to generate non-enzymatically by heme catalysis a large number of potent lipoperoxidation derivatives.
Study effects of HETE and 4-HNE. Among HZ-generated lipoperoxidation derivatives, HETEs (hydroxy-eicosatetraenoic acids) and 4-HNE (4-hydroxynonenal) are object of our studies. A) HZ-fed monocytes were unable to differentiate to fully active dendritic cells, and 15-HETE applied in the same range of concentrations as in HZ-fed cells reproduced those effect. B) HZ-fed monocytes produced and shed increased amounts of metallo-proteinases, that degrade sub-endothelia and are instrumental in extravasation of phagocytes. Again, 15-HETE reproduced this effect. In A) and B) we are concentrating on HETE mechanism of action. C) 4-HNE is produced in large amounts by native HZ, diffuses to membranes and forms stable adducts/crosslinks with/between membrane proteins. One consequence is rigidity of parasitized RBCs, and induced alterations to bystander unparasitized RBCs. D) 4-HNE shed by HZ-fed macrophages of erythroblastic islets is possibly instrumental in blockage of erythropoiesis and thus causal element of dyserythropoiesis in malarial anemia. In C) and D) we are trying to identify molecular targets of 4-HNE and its mechanism of action.
Study structure of highly purified food vacuoles. To better characterize the role of food vacuole (FV) in general and specifically in the process of HZ generation, we are currently performing proteomic studies (in collaboration with E. Lasonder, Radboud University Nijmegen) on highly purified FV.