Plasmodium falciparum is the causative agent responsible for the most severe form of human malaria, a disease that kills more than a million people a year, mostly young children in Africa. These protozoan parasites invade and ultimately destroy circulating red blood cells (RBCs) of their host, leading to severe anemia and the frequently lethal syndromes of cerebral malaria and pregnancy associated malaria. Over the course of an infection, small sub-populations of parasites arise that have an altered antigenic phenotype, thus avoiding the antibody response of the host. This process is referred to as antigenic variation and is responsible for the persistent nature of the disease as well as the waves of parasitemia frequently observed in P. falciparum infections. Antigenic variation of P. falciparum infected RBCs results from switches in expression between individual members of the multi-copy var gene family. Each var gene encodes a different form of a protein called PfEMP1. This protein is placed on the surface of the infected RBCs and mediates adhesion to specific receptors found on the endothelial surfaces of the blood vessel walls of the infected individual. This adhesion is responsible for many of the disease manifestations of infection with P. falciparum, including both cerebral malaria and pregnancy associated malaria. Only a single var gene is expressed at a time by any given parasite, thus determining both the antigenic phenotype of the infected cells as well as their adhesive properties. Therefore var gene expression is the heart of both antigenic variation and virulence of malaria infections. This project is designed to understand the molecular mechanisms the regulate var gene expression and antigenic variation by malaria parasites. Previous work has demonstrated that mutually exclusive expression of var genes involves specific modifications to the chromatin structure at each var gene, however how these modifications are coordinated to result in expression of only a single gene at a time out of a family of 60 remains unknown.
The specific aims of the project are 1) to identify and characterize chromatin boundary/insulator elements that regulate chromatin assembly at var genes, 2) to determine the role of noncoding RNAs in targeting chromatin assembly to var gene loci, and 3) to investigate the mechanism of translational regulation of a specific var gene implicated in pregnancy associated malaria. The experimental design relies on creating transgenic parasite lines using reporter genes and drug selectable markers to rapidly determine the role of these regulatory elements in controlling var gene expression. The long-term goals are to develop methods to disrupt the process of antigenic variation and thereby shorten the length of an infection and reduce its severity.

Public Health Relevance

Malaria remains one of the most important infectious disease killers in the world today, causing more than a million deaths annually, primarily of young children in sub-Saharan Africa. This project focuses on the ability of malaria parasites to avoid the human immune response and to cause severe disease. A better understanding of these processes will lead to new, novel forms of treatment that will help to relieve the enormous public health burden that malaria inflicts on the developing world.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Joy, Deirdre A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Schools of Medicine
New York
United States
Zip Code
Calhoun, Susannah F; Reed, Jake; Alexander, Noah et al. (2017) Chromosome End Repair and Genome Stability in Plasmodium falciparum. MBio 8:
Thorley-Lawson, David; Deitsch, Kirk W; Duca, Karen A et al. (2016) The Link between Plasmodium falciparum Malaria and Endemic Burkitt's Lymphoma-New Insight into a 50-Year-Old Enigma. PLoS Pathog 12:e1005331
Deitsch, Kirk W (2016) The Unifying Nature of Basic Science Research. PLoS Pathog 12:e1005329
Ukaegbu, Uchechi E; Deitsch, Kirk W (2015) The Emerging Role for RNA Polymerase II in Regulating Virulence Gene Expression in Malaria Parasites. PLoS Pathog 11:e1004926
Garg, Aprajita; Wesolowski, Donna; Alonso, Dulce et al. (2015) Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum. Proc Natl Acad Sci U S A 112:11935-40
Ukaegbu, Uchechi E; Zhang, Xu; Heinberg, Adina R et al. (2015) A Unique Virulence Gene Occupies a Principal Position in Immune Evasion by the Malaria Parasite Plasmodium falciparum. PLoS Genet 11:e1005234
Ukaegbu, Uchechi E; Kishore, Sandeep P; Kwiatkowski, Dacia L et al. (2014) Recruitment of PfSET2 by RNA polymerase II to variant antigen encoding loci contributes to antigenic variation in P. falciparum. PLoS Pathog 10:e1003854
Kirkman, Laura A; Lawrence, Elizabeth A; Deitsch, Kirk W (2014) Malaria parasites utilize both homologous recombination and alternative end joining pathways to maintain genome integrity. Nucleic Acids Res 42:370-9
Kishore, Sandeep P; Stiller, John W; Deitsch, Kirk W (2013) Horizontal gene transfer of epigenetic machinery and evolution of parasitism in the malaria parasite Plasmodium falciparum and other apicomplexans. BMC Evol Biol 13:37
Bancells, Cristina; Deitsch, Kirk W (2013) A molecular switch in the efficiency of translation reinitiation controls expression of var2csa, a gene implicated in pregnancy-associated malaria. Mol Microbiol 90:472-88

Showing the most recent 10 out of 34 publications