Unit | Malaria Gene Regulation

The Malaria Gene Regulation Unit aims to understand the molecular basis of two of the most important survival strategies of malaria blood-stage parasites - antigenic variation and gametocyte formation. Antigenic variation allows the parasites to evade the human immune response and establish a chronic blood infection. Gametocyte formation ensures the transmission of malaria from one human host to the next via the mosquito vector.

Our Research Focus: Epigenetics of Antigenic Variation and Sexual Commitment

Antigenic variation and sexual commitment are absolutely essential for parasite survival. While antigenic variation secures the long-term survival of the parasite population in the bloodstream, sexual commitment provides a continuous source of gametocytes, ultimately facilitating human-to-human transmission of malaria. Interestingly, these seemingly unrelated processes are controlled by a similar logic in the regulation of gene expression.

Both antigenic variation and sexual commitment are based on clonally variant gene expression, and both processes are epigenetically controlled by heterochromatin protein 1 (HP1), an evolutionarily conserved silencing factor. In P. falciparum, HP1 silences hundreds of genes encoding variable surface antigens, including all members of the var/PfEMP1 family. Stochastic activation and switches in their expression are responsible for antigenic variation and immune evasion. Apart from antigenic variation genes, HP1 also silences the locus encoding AP2-G, a master transcription factor (TF) essential for sexual commitment and gametocyte differentiation. It appears that HP1-dependent silencing of ap2-g keeps parasites in asexual proliferation mode, whereas targeted activation of ap2-g triggers sexual conversion, cell cycle exit and gametocyte differentiation.

Our research seeks to dissect and understand the molecular players and pathways that regulate these vital processes.