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MALMASQ Report Summary

Project ID: 615412
Funded under: FP7-IDEAS-ERC
Country: Israel

Mid-Term Report Summary - MALMASQ (Understanding immune evasion by malaria parasites)

The deadliest form of human malaria is caused by the protozoan parasite, Plasmodium falciparum, which annually infects millions worldwide. Its virulence 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. Antigenic variation is achieved through switches in expression of hypervariable surface ligands named PfEMP1. These 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, a phenomenon known as "allelic exclusion". How cells specifically express only a single gene among numerous equivalent copies within their genomes is one of the unsolved mysteries in the field of eukaryotic gene expression. The molecular mechanisms that underlie mutually exclusive gene expression, are the key for understanding the virulence of P. falciparum.
The rational of this project is that understanding the molecular mechanisms by which the parasite evades human immune attack would lead to the development of novel approaches that disrupts this ability, giving the human immune system an opportunity to clear the infection and overcome the disease.
We approach mutually exclusive expression as the interplay between mechanisms that keep the entire var gene family transcriptionally silent by default and mechanisms of “choice” for the single gene that will be activated, followed with its epigenetic imprinting as the active gene. We found that the ability of var intron to function as a silencer on the var promoter is mediated by insulator-like DNA elements which are bound by specific nuclear proteins. We identified a short list of nuclear proteins that specifically bind these elements and determine their role in var gene regulation by forward and reverse genetic approaches, followed by biochemical analyses and super resolution microscopy. We made significant progress in understanding how one var gene is chosen for activation. We found that var-specific antisense lncRNA molecules incorporate into chromatin, hybridize DNA, thus specifically associate with the active gene at the time when it is active. We were able to activate a silent var gene by expressing its specific antisense lncRNAs in a dose dependent manner and one the other hand were able to down regulate an active var gene and erase its epigenetic memory by interfering with its antisense transcripts. We also identified proteins that specifically bind these lncRNAs and test a model by which they determine how parasites select a single gene for expression while the rest of the family is maintained silenced.
The outcome of this project is new concepts for disrupting the parasite’s ability to evade immune attack, which could be exploited for the discovery of novel targets for drug and vaccine development. In addition, monoallelic expression is a fundamental yet poorly understood phenomenon in the field of eukaryotic gene expression. It is therefore expected that this project will contribute to our basic understanding of genetic mechanisms, beyond the topic of antigenic variation in malaria.

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