Project description:Red blood cell invasion by the malaria parasite is coordinated through recruitment of a bromodomain protein by the PfAP2-I transcription factor
Project description:Little is known about the role of the three Jumonji C (JmjC) enzymes in Plasmodium falciparum (Pf). Here, we show that JIB-04 and other established inhibitors of mammalian JmjC histone demethylases kill asexual blood stage parasites and are even more potent at blocking gametocyte development and gamete formation. In late stage parasites, JIB-04 increased levels of trimethylated lysine residues on histones, suggesting the inhibition of P. falciparum Jumonji demethylase activity. These epigenetic defects coincide with deregulation of invasion, cell motor, and sexual development gene programs, including gene targets coregulated by the PfAP2-I transcription factor and chromatin-binding factor, PfBDP1. Mechanistically, we demonstrate that PfJmj3 converts 2-oxoglutarate to succinate in an iron-dependent manner consistent with mammalian Jumonji enzymes, and this catalytic activity is inhibited by JIB-04 and other Jumonji inhibitors. Our pharmacological studies of Jumonji activity in the malaria parasite provide evidence that inhibition of these enzymatic activities is detrimental to the parasite.
Project description:Periodic fever is the most characteristic clinical feature of human malaria. However, how parasites survive malarial febrile episodes, which often involve temperatures of >40ºC, is not known. To understand the molecular basis of heat shock (HS) resistance in Plasmodium falciparum, we took advantage of previously developed P. falciparum lines adapted to periodic HS (3D7-A-HS) and their non-selected controls maintained in parallel (3D7-A). Their ability to adapt in only a few cycles suggested that the parental parasite population contained a selectable subset of parasites resistant to HS. Transcriptomic analysis of both 3D7-A-HS and 3D7-A was used to study the differences at a transcriptional level that could be related with the HS-resistant phenotype.
