Plasmodium falciparum is the causative agent responsible for the most severe form of human malaria, a disease that kills more than 800,000 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 the both the antigenic phenotype of the infected cells as well as their adhesive properties. Therefore var gene expression is at the heart of both antigenic variation and virulence of malaria infections. The long-term objectives of this project are to understand the molecular mechanisms that regulate var gene expression and antigenic variation by malaria parasites. Previous work identified a unique regulatory element found in all var genes that is necessary for proper regulation of each var gene.
The specific aims of the project are designed to determine exactly how this element exerts its influence on the gene family and how switching between var genes is coordinated.
Aim 1 investigates the recruitment of a specific histone modifier called PfSET2 to var genes through direct interactions with RNA pol II during the transcription of noncoding RNAs.
The second aim i nvestigates the role of an unusual var gene in coordinating the switching process. Collectively, this project will contribute to the ongoing effort 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 up to 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI052390-13A1
Application #
8985822
Study Section
Special Emphasis Panel (ZRG1-IDM-P (02))
Program Officer
Joy, Deirdre A
Project Start
2002-06-01
Project End
2020-05-31
Budget Start
2015-06-15
Budget End
2016-05-31
Support Year
13
Fiscal Year
2015
Total Cost
$423,750
Indirect Cost
$173,750
Name
Weill Medical College of Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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

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