Swiss TPH

The 60-member var gene family encodes the major P. falciparum virulence factor PfEMP1, an important contributor to severe malaria outcomes. var gene expression is controlled by an unknown mechanism of mutually exclusive transcription – or singular gene choice – and switches in locus activation lead to antigenic variation of PfEMP1 and immune evasion. var genes are located subtelomerically in heterochromatic domains that also carry members of several other poorly understood antigen gene families such as rif, stevor, pfmc-2tm, phist and hyp.
We used functional mapping experiments to identify regulatory var promoter elements that mediate promoter activation and singular gene choice (Brancucci and Witmer et al., submitted). These sequences are now used to identify interacting factors by complementary efforts involving gel shift assays, affinity purification/LC-MS/MS, and yeast one-hybrid screens. Successful identification of such regulators will allow us to understand the mechanisms responsible for singular gene choice in much greater detail. We are also interested in the question as to whether the parasite employs a logic of singular gene choice also to the transcription of non-var gene families; i.e is mutually exclusive transcription a conserved mechanisms used by the parasite to evade adaptive immune responses? To answer this question we applied a comparative whole transcriptome profiling approach using a panel of transgenic reporter lines (in collaboration with Zbynek Bozdech and Peter Preiser; Nanyang Technological University, Singapore) (Witmer et al., submitted).