Dual ICAM1 and EPCR binding PfEMP1 proteins and cerebral malaria

Is cerebral malaria associated with specific adhesive properties of infected blood cells?

This collaborative project, with Anja Jensen’s group, started by exploring a group of PfEMP1 proteins found on surfaces of malaria-infected red blood cells which bind to the human receptor ICAM-1. Frank Lennartz determined the structure of a PfEMP1 domain bound to ICAM-1. In parallel, Anja analysed the sequences of a set of ICAM-1 binding domains. Both revealed conservation of a sequence motif which defines a group of ICAM-1 binding domains.

icam

Analysing PfEMP1 sequences which contain this sequence motif provided a surprise. PfEMP1 proteins contain multiple individual domains in a linear sequence and all PfEMP1 with an ICAM-1 binding domains baring the sequence motif contained a neighbouring EPCR-binding domain. Studies with both proteins and parasites showed that these PfEMP1 could bind simultaneously to both human receptors and that this increased their binding strength.

Parasites which produce PfEMP1 that contain EPCR-binding domains had previously been shown to be more commonly found in patients with severe childhood malaria. How about these dual-binding PfEMP1? Sequence analysis of PfEMP1 taken from patients with cerebral malaria, severe anaemia or uncomplicated malaria showed the dual-binders to be most commonly found associated with cases of cerebral malaria. Perhaps the capacity to bind both EPCR and ICAM-1 leads to increased accumulation or increased inflammation in the brain?

This study therefore identifies dual ICAM-1 and EPCR-binding PfEMP1 as a potential target to prevent the severe outcomes of cerebral malaria.  

Lennartz, F., Adams, Y., Bengtsson, A., Olsen, R.W., Turner, L., Ndam, N.T., Ecklu-Mensah, G., Moussiliou, A., Ofori, M.F., Gamain, B., Lusingu, J.P., Petersen, J.E.V, Wang, C.W., Nunes-Silva, S., Jespersen, J.S., Lau, C.K.W., Theander, T.G., Lavstsen, T., Hviid, L., Higgins, M.K.*, JensenA.T.R * (2017) Structure-guided identification of a family of dual receptor binding PfEMP1 that are associated with cerebral malaria. Cell Host and Microbe 21 403-414 (* equal corresponding)