: Malaria remains one of the leading causes of morbidity and mortality in the developing world. The disease is caused by protozoan parasites that invade and ultimately destroy circulating red blood cells of their host, leading to severe anemia and the frequently lethal syndrome of cerebral malaria. These parasites have evolved a complex mechanism of immune evasion whereby, 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 of antigenic variation and is responsible for the persistent nature of the disease as well as the waves of parasitemia frequently observed in individuals infected by P. falciparum. The variation in antigenic phenotype is the result of switches in expression between individual members of the multicopy var gene family. This family consists of approximately 40-50 genes that encode the predominant antigenic determinant, a protein called PIEMPI. Only a single var gene is expressed at a time by any given parasite, thus determining the antigenic type of the infected cell. Changes in var gene expression and the resulting antigenic variation appear to be controlled at the level of transcription. The objective of this proposal is to determine the molecular mechanisms that maintain all but a single var gene in a transcriptionally silent state. The hypothesis to be tested is that var promoters are silenced through the assembly of a condensed, heterochromatic state and that chromatin modification and remodeling regulates expression of var genes and antigenic variation in Plasmodium falciparum. The experimental design exploits the recent discovery that elements upstream of var promoters act in a cooperative fashion with a conserved intron found in all var genes to silence transcription of all but a single gene. This transcriptionally silent state can be assembled on transfected episomes containing a reporter gene flanked by a var promoter and intron. Using this episomal system, the chromatin structure and subnuclear localization of silent and active var promoters will be determined. In addition, the specific DNA elements necessary for var gene silencing and activation will be identified, and the sequence requirements for DNA elements to functions as silencers or activators elucidated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052390-07
Application #
7425348
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Joy, Deirdre A
Project Start
2002-06-01
Project End
2009-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
7
Fiscal Year
2008
Total Cost
$351,604
Indirect Cost
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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