A5052238251- Malaria Research and Control
- Invertebrate Immune Response Mechanisms
- Mosquito-borne diseases and control
- HIV/AIDS drug development and treatment
- Trypanosoma species research and implications
- Biochemical and Molecular Research
- HIV Research and Treatment
- RNA and protein synthesis mechanisms
- Insect symbiosis and bacterial influences
- Aquaculture disease management and microbiota
- Research on Leishmaniasis Studies
- Insect Resistance and Genetics
- Metabolomics and Mass Spectrometry Studies
- Complement system in diseases
- Drug Transport and Resistance Mechanisms
- Pneumocystis jirovecii pneumonia detection and treatment
- Polyamine Metabolism and Applications
- Sperm and Testicular Function
- vaccines and immunoinformatics approaches
- Pharmacological Effects of Natural Compounds
- Cultural Industries and Urban Development
- MicroRNA in disease regulation
- Healthcare Quality and Management
- Computational Drug Discovery Methods
- Metabolism and Genetic Disorders
Center for Biologics Evaluation and Research
2019-2023
Pennsylvania State University
2016-2022
United States Food and Drug Administration
2019
Food and Drug Administration
2019
California University of Pennsylvania
2015
Princeton University
2010-2015
Drexel University
2007-2011
Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome of 262
Abstract In the malaria parasite Plasmodium falciparum , switch from asexual multiplication to sexual differentiation into gametocytes is essential for transmission mosquitos. The transcription factor PfAP2-G a key determinant of commitment that orchestrates this crucial cell fate decision. Here we identify direct targets and demonstrate it dynamically binds hundreds sites across genome. We find transcriptional activator early gametocyte genes, differences in occupancy between derived via...
New antimalarial drugs are urgently needed to control drug-resistant forms of the malaria parasite Plasmodium falciparum. Mitochondrial electron transport is target both existing and new antimalarials. Herein, we describe 11 genetic knockout (KO) lines that delete six eight mitochondrial tricarboxylic acid (TCA) cycle enzymes. Although all TCA KOs grew normally in asexual blood stages, these metabolic deficiencies halted life-cycle progression later stages. Specifically, aconitase KO...
The threat of widespread drug resistance to frontline antimalarials has renewed the urgency for identifying inexpensive chemotherapeutic compounds that are effective against Plasmodium falciparum, parasite species responsible greatest number malaria-related deaths worldwide. To aid in fight malaria, a recent extensive screening campaign generated thousands lead with low micromolar activity blood stage parasites. A subset these leads been compiled by Medicines Malaria Venture (MMV) into...
Genome-wide analysis of transcription in the malaria parasite Plasmodium falciparum has revealed robust variation steady-state mRNA abundance throughout 48-h intraerythrocytic developmental cycle (IDC), suggesting that this process is highly dynamic and tightly regulated. Here, we utilize rapid 4-thiouracil (4-TU) incorporation via pyrimidine salvage to specifically label, capture, quantify newly-synthesized RNA transcripts at every hour IDC. This high-resolution global transcriptome...
Malaria pathogenesis relies on sexual gametocyte forms of the malaria parasite to be transmitted between infected human and mosquito host but molecular mechanisms controlling gametocytogenesis remains poorly understood. Here we provide a high-resolution transcriptome Plasmodium falciparum as it commits develops through gametocytogenesis.The gametocyte-associated is significantly different from that asexual parasites, with dynamic gene expression shifts characterizing early, intermediate...
Abstract Gene expression in Plasmodia integrates post-transcriptional regulation with epigenetic marking of active genomic regions through histone post-translational modifications (PTMs). To generate insights into the importance PTMs to entire asexual and sexual developmental cycles parasite, we used complementary comparative quantitative chromatin proteomics identify functionally characterise 8 distinct life cycle stages P. falciparum parasites. ~500 individual were identified which 106...
Abstract Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are major determinant of this lethal human malaria parasite. Here, we describe P. lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F L272F), causing development enlarged food vacuoles. These parasites also have increased sensitivity and some other quinoline antimalarials, but exhibit no minimal change artemisinins, when compared with parental strains. A...
Abstract Differentiation from asexual blood stages to mature sexual gametocytes is required for the transmission of malaria parasites. Here, we report that ApiAP2 transcription factor, PfAP2‐G2 (PF3D7_1408200) plays a critical role in maturation Plasmodium falciparum gametocytes. binds promoters wide array genes are expressed at many parasite life cycle. Interestingly, also find binding within gene body almost 3,000 genes, which strongly correlates with location H3K36me3 and several other...
Previous studies demonstrated that Plasmodium falciparum strain D10 became highly resistant to the mitochondrial electron transport chain (mtETC) inhibitor atovaquone when mtETC was decoupled from pyrimidine biosynthesis pathway by expressing fumarate-dependent (ubiquinone-independent) yeast dihydroorotate dehydrogenase (yDHODH) in parasites. To investigate requirement for activity P. with different genetic backgrounds, we integrated a single copy of yDHODH gene into genomes D10attB,...
To capture the transcriptional dynamics within proliferating cells, methods to differentiate nascent transcription from preexisting mRNAs are desired. One approach is label newly synthesized mRNA transcripts in vivo through incorporation of modified pyrimidines. However, human malaria parasite, Plasmodium falciparum, incapable pyrimidine salvage for biogenesis. cellular during development, we engineered parasites that can pyrimidines expression a single bifunctional yeast fusion gene,...
Although mitochondrial electron transport is a validated target of the antimalarial drug atovaquone, molecular details underlying parasite demise are unclear. We have shown that critical function in blood-stage Plasmodium falciparum to support pyrimidine biosynthesis. Here, we explore effects alone and combination with proguanil, on P. viability. Our results suggest inhibition depend upon erythrocytic stage parasites duration exposure. Ring- schizont-stage most resilient treatment can...
The life cycle of the malaria parasite Plasmodium falciparum is tightly regulated, oscillating between stages intense proliferation and quiescence. Cyclic 48-hour asexual replication markedly different from cell division in higher eukaryotes, mechanistically poorly understood. Here, we report tight synchronisation parasites during early phases by exposure to DL-α-difluoromethylornithine (DFMO), which results depletion polyamines. This induces an inescapable arrest G1 (~15 hours...
DNA microarrays have been a valuable tool in malaria research for over decade but remain limited use part due their relatively high cost, poor availability, and technical difficulty. With the aim of alleviating some these factors next-generation genome-wide transcriptome analysis both Plasmodium falciparum berghei using Agilent 8 x 15 K platform were designed.Probe design was adapted from previously published methods based on most current transcript predictions available at time P. or...
Cripowellins from Crinum erubescens are known pesticidal and have potent antiplasmodial activity. To gain mechanistic insights to this class of natural products, studies determine the timing action cripowellins within asexual intraerythrocytic cycle Plasmodium falciparum were performed led observation that products induced reversible cytostasis in ring stage first 24 h treatment. The transcriptional program necessary for P. progress through life is well characterized. Whole transcriptome...
Gene expression DNA microarrays have been vital for characterizing whole-genome transcriptional profiles. Nevertheless, their effectiveness relies heavily on the accuracy of genome sequences, annotation gene structures, and sequence-dependent performance individual probes. Currently available arrays malaria parasite Plasmodium falciparum rely an average 2 probes per gene, usually positioned near 3' end genes; consequently, existing designs are prone to measurement bias cannot capture...
Summary In the malaria parasite Plasmodium falciparum , switch from asexual multiplication to sexual differentiation into gametocytes is essential for transmission mosquitos. One of key determinants commitment transcription factor PfAP2-G, which has been proposed orchestrate this crucial cell fate decision by driving expression gametocyte genes. We show conclusively that PfAP2-G a transcriptional activator genes and identify earliest known markers expressed during commitment. Remarkably, we...
The continued emergence of drug-resistant Plasmodium falciparum parasites hinders global attempts to eradicate malaria, emphasizing the need identify new antimalarial drugs. Attractive targets for chemotherapeutic intervention are cytochrome (cyt) bc 1 complex, which is an essential component mitochondrial electron transport chain (mtETC) required ubiquinone recycling and mitochondrially localized dihydroorotate dehydrogenase (DHODH) critical de novo pyrimidine synthesis.
SUMMARY: To capture the transcriptional dynamics within proliferating cells, methods to differentiate nascent transcription from pre-existing mRNAs are desired. One approach is label newly synthesized mRNA transcripts in vivo through incorporation of modified pyrimidines. However, human malaria parasite, Plasmodium falciparum , incapable pyrimidine salvage for biogenesis. cellular during development, we have engineered parasites that can pyrimidines expression a single bifunctional yeast...