WEHI Wednesday Seminar hosted by Professor Alan Cowman
 

Ben Seager
PhD Student – Cowman Laboratory, Infectious Diseases & Immune Defence division – Infection, Inflammation & Immunity Theme, WEHI (this is a PhD Completion seminar)

A conserved molecular mechanism of erythrocyte invasion by malaria parasites

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session

Malaria parasites invade erythrocytes through a complex multi-step process that involves many host-parasite interactions. In Plasmodium falciparum, the deadliest species of the parasite, the invasion protein PfRh5 assembles into a complex to bind its receptor basigin on the erythrocyte surface. Recent work has revealed two novel members of this complex, PfPTRAMP and PfCSS, form a heterodimeric platform for PfRipr, PfCyRPA, and PfRh5 binding. The PTRAMP-CSS-Ripr-CyRPA-Rh5 (PCRCR) complex, and its engagement with basigin, is essential for P. falciparum invasion. PfRh5 is not present in all species of malaria, however PTRAMP, CSS and Ripr orthologues are present across the entire Plasmodium genus. We sought to investigate these conserved proteins in other species of malaria to further dissect the essentiality of these proteins for Plasmodium invasion more broadly. Recombinantly expressed P. vivax PTRAMP and CSS form a disulphide-linked heterodimer (PvPC) as described in P. falciparum. PvRipr engages PvPC via PTRAMP to form a three-membered complex which we term PvPCR, and we show that P. knowlesi, a zoonotic form of malaria, assembles an identical three-membered complex. Using negative stain electron microscopy and X-ray crystallography we have structurally characterised key features of the PvPCR complex. We have identified a potential Rh5-equivalent in P. vivax which weakly binds to the PvPCR complex and is able to bind erythrocytes. We have raised antibodies and nanobodies to the P. vivax complex components and find that they are highly cross-reactive with the P. knowlesi orthologues and show some cross-reactivity with P. falciparum. Ex-vivo growth inhibition assays on Cambodian P. vivax isolates confirms the role of these proteins in invasion. Taken together, we have demonstrated that a three-membered complex consisting of PTRAMP, CSS and Ripr is conserved in three species of Plasmodium, strongly suggesting a common invasion scaffold across the entire genus. Together with our inhibition studies, these data suggest that PTRAMP, CSS and Ripr may represent a conserved invasion mechanism with implications for cross-species vaccine development for the control of both P. vivax and P. falciparum malaria.

All welcome!