Platelet derived growth factor receptor \u03b2 (PDGFR\u03b2) is a host receptor for the human malaria parasite adhesin TRAP

Ryan W J Steel,Nicholas Dambrauskas,Sudhir Kumar,Will Betz,Thao Nguyen,D Noah Sather,Jim Freeth,Vladimir Vigdorovich,Bridget S Fisher,Debashree Goswami,Helen Thomas,Silvia A Arredondo,Brandon K Wilder,Jo Soden,Kristian E Swearingen,Stefan H I Kappe,Robert L Moritz,Nelly Camargo,Sara Carbonetti

doi:10.1038/s41598-021-90722-5

Abstract

Following their inoculation by the bite of an infected Anopheles mosquito, the malaria parasite sporozoite forms travel from the bite site in the skin into the bloodstream, which transports them to the liver. The thrombospondin-related anonymous protein (TRAP) is a type 1 transmembrane protein that is released from secretory organelles and relocalized on the sporozoite plasma membrane. TRAP is required for sporozoite motility and host infection, and its extracellular portion contains adhesive domains that are predicted to engage host receptors. Here, we identified the human platelet-derived growth factor receptor β (hPDGFRβ) as one such protein receptor. Deletion constructs showed that the von Willebrand factor type A and thrombospondin repeat domains of TRAP are both required for optimal binding to hPDGFRβ-expressing cells. We also demonstrate that this interaction is conserved in the human-infective parasite Plasmodium vivax, but not the rodent-infective parasite Plasmodium yoelii. We observed expression of hPDGFRβ mainly in cells associated with the vasculature suggesting that TRAP:hPDGFRβ interaction may play a role in the recognition of blood vessels by invading sporozoites.

Highlights

Following their inoculation by the bite of an infected Anopheles mosquito, the malaria parasite sporozoite forms travel from the bite site in the skin into the bloodstream, which transports them to the liver
We found that P. falciparum TRAP (PfTRAP) interacts with human platelet-derived growth factor receptor β and further investigated this interaction using HEK293F cells overexpressing this receptor
We further studied the domains of PfTRAP that were required for this interaction, and whether the engagement of PDGFRβ by thrombospondin-related anonymous protein (TRAP) is conserved in other Plasmodium species

Summary

Introduction

Following their inoculation by the bite of an infected Anopheles mosquito, the malaria parasite sporozoite forms travel from the bite site in the skin into the bloodstream, which transports them to the liver. TRAP is required for sporozoite motility and host infection, and its extracellular portion contains adhesive domains that are predicted to engage host receptors. Deletion constructs showed that the von Willebrand factor type A and thrombospondin repeat domains of TRAP are both required for optimal binding to hPDGFRβ-expressing cells. Parasite adhesion proteins enabling sporozoite gliding motility, tissue traversal and infection are released from a set of apical organelles, the micronemes and rhoptries[10]. An important sporozoite micronemal protein called the thrombospondin-related anonymous protein (TRAP), is required for both sporozoite motility as well as hepatocyte infection[11].

Methods

Results

Conclusion