Malaria is one of the most devastating parasitic diseases worldwide, responsible for an estimated 207 million clinical cases and 627,000 deaths in 2012 alone. Major virulence factors of malaria are parasite replication in the blood that leads to severe anemia, and in the most lethal form, Plasmodium falciparum-infected red cells block capillaries of organs in a phenomenon linked to lethal outcomes. Blood-stage replication is part of a complex life cycle in multiple hosts involving both sexual and asexual stages that requires very tight developmental control of gene expression. Recent studies in our lab have implicated post-transcriptional control as a major player during parasite development in certain types of genes associated with virulence. The mechanisms of post-transcriptional regulatory control represent new potential targets for drug intervention. We recently demonstrated that a knock- out of the P. falciparum CAF1 gene altered expression of ~20% of the genome, dramatically shifting expression of virulence genes in late trophozoites and many genes of late-stage proteins involved in parasite replication (egress and invasion). In other organisms, CAF1 is a major player controlling gene expression as a deadenylase regulating mRNA decay in the cytoplasm and as part of the CCR4-NOT complex regulating transcription in the nucleus. We hypothesize that CAF1 is integral for proper control of P. falciparum gene expression as a post-transcriptional regulator. The long-term objective of these studies is to understand P. falciparum post-transcriptional regulatory mechanisms to identify key players suitable as novel drug targets. We seek here to elucidate some of the mechanisms behind this regulatory control in P. falciparum by using our existing CAF1 knockout and gene expression data, computational tools and other biochemical assays. Further, we believe that illuminating the mechanisms behind the post-transcriptional layer of gene regulation will yield unique insights into P. falciparum biology and has the potential to provide valuable information for the development of new interventions targeting parasite egress and invasion.
Malaria is one of the most devastating parasitic diseases worldwide, responsible for an estimated 207 million clinical cases and 627,000 deaths in 2012 alone. This project will study the parasite's gene regulatory mechanisms to provide valuable information for the identification of new drug targets.
|Thomas, Phaedra; Sedillo, Jennifer; Oberstaller, Jenna et al. (2016) Phenotypic Screens Identify Parasite Genetic Factors Associated with Malarial Fever Response in Plasmodium falciparum piggyBac Mutants. mSphere 1: