"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"". These antigenic switches allow the parasite to avoid the human immune response and maintain a long-term infection. How mutually exclusive expression is regulated is still elusive.
The rationale of the proposed study is that understanding the molecular mechanisms by which the parasite evade human immune attack would lead to the development of therapeutic approaches that disrupt this ability and would give the human immune system an opportunity to clear the infection and overcome the disease.
I will focus this research project on understanding one of the unsolved mysteries in gene expression which is responsible for regulating antigenic variation in P. falciparum: the nature of ""communication"" between genes that allows expression of only a single gene at a time and the selection of the ""chosen one"" for activation while the rest of the gene family remains silent.
The expected outcome of this knowledge is new concepts for disrupting the parasite’s ability to evade immune attack which will be exploited for the discovery of novel targets for drug and vaccine development. In addition, it will unravel mechanisms of allelic exclusion that extend beyond malaria virulence into fundamental aspect of gene expression in other organisms."
Field of science
- /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
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