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The role of a nuclear expression site in the regulation of virulence genes in malaria parasites

Objective

The deadliest form of human malaria is caused by the protozoan parasite, Plasmodium falciparum, which annually infects millions worldwide. The virulence of P. falciparum is attributed to its ability to evade the human immune system, by modifying the host red blood cell surface to adhere to the vascular endothelium and to undergo antigenic variation. The main cell surface ligands responsible for both cytoadherence and antigenic variation are members of the P. falciparum Erythrocyte Membrane Protein-1 (PfEMP1) family. These polymorphic proteins are encoded by a multi-copy gene family called var. Each individual parasite expresses a single var gene at a time, whereas the remaining ~60 var genes found in its genome are maintained in a transcriptionally silent state. Switches in PfEMP1 expression allow the parasite to avoid the human immune response and maintain a long-term infection. The regulation of var gene expression is therefore responsible for both immune evasion and the pathogenicity of the disease. Mutually exclusive expression and antigenic switching of var genes is epigenetically regulated at the level of transcription. This was recently demonstrated to involve chromatin modification, subnuclear localization, promoter/promoter interactions, and sterile RNAs. However, our understanding of the molecular mechanisms by which var genes are regulated is still elusive, particularly the aspects of var gene activation. I hypothesize that there exists a specific subnuclear var expression site that is involved in var gene activation. To this end the goals of the proposed research are: 1) to determine the capacity of the postulated var expression site and its role in var gene expression; 2) to determine the specificity of the expression site as a limiting factor for var gene regulation. This knowledge could lead to ways of disrupting the parasite’s ability to evade immune attack and could be exploited for the discovery of novel targets for drug and vaccine development.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/rna
  • /medical and health sciences/health sciences/infectious disease/malaria
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /medical and health sciences/basic medicine/immunology
  • /natural sciences/biological sciences/genetics and heredity/genome

Call for proposal

FP7-PEOPLE-2007-4-3-IRG
See other projects for this call

Funding Scheme

MC-IRG - International Re-integration Grants (IRG)

Coordinator

THE HEBREW UNIVERSITY OF JERUSALEM
Address
Edmond J Safra Campus Givat Ram
91904 Jerusalem
Israel
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 100 000
Administrative Contact
Eran Vardi (Dr.)