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  1. Biologics Research Projects

Novel Methods to Detect Malaria Biomarkers for Evaluation of Vaccine Safety and Efficacy

Heather J. Painter, PhD

Office of Vaccines Research and Review
Division of Bacterial, Parasitic and Allergenic Products
Laboratory of Mucosal Pathogens and Cellular Immunology

[email protected]

Biosketch

Heather J. Painter, PhD, is a principal investigator in the Laboratory of Mucosal Pathogens and Cellular Immunology.  Dr. Painter received her PhD in molecular, cell biology & genetics from the Drexel University College of Medicine. After completing her postdoctoral research at Princeton University and Pennsylvania State University, she joined the Division of Bacterial, Parasitic, and Allergenic Products, Office of Vaccines Research and Review, at CBER in 2019.  Her laboratory evaluates the feasibility and new approaches for creation of anti-malaria vaccines by identifying the molecular processes involved in parasite development, creation of novel assays to detect the developing parasite in human populations and defining biomarkers of infection and immunity and creation of appropriate assays, including nascent transcriptome analysis.

General Overview

Malaria is a devastating disease that afflicts nearly half a billion people worldwide, causing 1-2 million deaths annually, mostly among children and pregnant women. Although this disease is not common in the US, travelers to or from countries where malaria is endemic are at risk for infection.

The most lethal causative agent of the disease is the parasite Plasmodium falciparum, which is transmitted from an infected female Anopheles mosquito to humans. Currently, there is neither an FDA-licensed preventive vaccine nor a highly effective chemotherapy against the transmissible parasites. Blocking transmission of the parasite is a major step toward developing and evaluating a safe and effective malaria vaccine. However, little is known about parasite biology during the stages of development. The goal of our research program is to fill these gaps and to facilitate the development and evaluation of prophylactic malaria vaccines and other therapies.

Our laboratory seeks to create unique tools to identify novel biomarkers that help us to predict infection, transmission, and severity of the disease. These tools will enable us to evaluate the efficacy of malaria vaccines and chemotherapies. This work also has the potential to identify new therapeutic targets.

Scientific Overview

The human pathogen Plasmodium falciparum, the causative agent of malaria, has a complex life cycle that includes its development in multiple tissues within the human host and mosquito vector. During human infection, the parasite predominantly replicates asexually every 48 hours, going from one to up to 24 new parasites in every cycle. However, in one to three percent of these cycles the parasite undergoes sexual differentiation, producing male and female gametocytes. These gametocytes are transmitted to the mosquito vector, completing the lifecycle of the parasite. Development of the Plasmodium parasite within various cell types involves the regulation of nascent mRNA transcription, as well as post-transcriptional mechanisms that impact mRNA stability.

In most eukaryotic systems, post-transcriptional regulation is mediated by the interaction of nascent mRNAs with specific RNA binding proteins (RNABPs). Our studies focus on the regulation of mRNA dynamics during the sexual stage of parasite development, a stage that has been relatively inaccessible to such studies until recently. By genetically engineering P. falciparum parasites to enable them to scavenge pyrimidine precursors, we can now feed them modified 4-thiouracil (4-TU), which they readily incorporate into newly transcribed RNA. These thiolated RNAs allow us to specifically address questions regarding RNA metabolism by capturing and identifying these nascent RNAs, as well as their RNABPs.

To enhance our understanding of parasite development and transmission, we are directly profiling whole-genome real-time transcription and mRNA stabilization, as well as identifying the molecular factors that regulate gene expression. Ultimately, these studies will aid in the evaluation of anti-malaria treatments and could result in novel intervention strategies.

Publications

  1. Nature Communications. (2020) 11 (1), 1-13.
    Dissecting the role of PfAP2-G in malaria gametocytogenesis.
    Josling GA, Venezia J, Orchard L, Russell TJ, Painter HJ, Llinás M.
  2. BMC Genomics. (2019) 20 (1), 1-16.
    Intricate hierarchical transcriptional control regulates Plasmodium falciparum sexual differentiation.
    Van Biljon R, van Wyk R, Orchard L, Reader J, Painter HJ, Niemand J, Llinás M, Birkholtz LM.
  3. Scientific Reports. (2018) 8:16581, 1-14.
    Inducing controlled cell cycle arrest and re-entry during asexual proliferation of Plasmodium falciparum malaria parasites.
    Van Biljion R, Niemand J, van Wyk R, Clark K, Verlinden B, Abrie C, von Gruning H, Smidt W, Smit A, Reader J, Painter HJ, Llins M, Doerig C, Birkholtz LM.
  4. Nature Communications. (2018) 9 (1), 2656.
    Genome-wide real-time in vivo transcriptional dynamics during Plasmodium falciparum blood-stage development
    Painter HJ, Chung NC, Sebastian A, Albert I, Storey J, Llinás M.
  5. Science (2017) Jan 12: 359 (6372), 191-199.
    Mapping the malaria parasite drug-able genome using in vitro evolution and chemogenomics.
    Cowell AN, Istvan ES, Lukens AK, Gomez-Lorenzo MG, Vanaerschot M, Sakata-Kato T, Flannery EL, Magistrado P, Owen E, Abraham M, LaMonte G, Painter HJ, Williams RM, Franco V, Linares M, Arriaga I, Bopp S, Corey VC, Gnadig NF, Coburn-Flynn O, Reimer C, Gupta P, Murithi JM, Fuchs O, Sasaki E, Kim SW, Teng C, Wang LT, Willis P, Siegel D, Tanaseichuk O, Zhong Y, Zhou Y, Llinás M, Ottilie S, Gamo F, Lee MCS, Goldberg DE, Fidock DA, Wirth DF, Winzeler EA.
  6. PLoS ONE (2017) 12(11):e0187595.
    Simultaneous genome-wide gene expression and transcript isoform profiling in the human malaria parasite.
    Turnbull LB, Siwo GH, Button-Simons KA, Tan A, Checkley LA, Painter HJ, Llinás M, Ferdig MT.
  7. Genome Research. (2017) Jun;27(6):1074-1086.
    Capturing in vivo RNA transcriptional dynamics from the malaria parasite Plasmodium falciparum.
    Painter HJ, Carrasaquilla M, Llinás M.
  8. Scientific Reports (2017) Apr 4;7(1):607.
    Quantitative chromatin proteomics reveals a dynamic histone post-translational modification landscape that defines asexual and sexual Plasmodium falciparum parasites.
    Coetzee N, Sidoli S, van Biljon R, Painter HJ, Llinás M, Garcia BA, Birkholtz L.

 

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