Plasmodium falciparum infected erythrocytes can bind to host receptors integrins \u03b1V\u03b23 and \u03b1V\u03b26 through DBL\u03b41_D4 domain of PFL2665c PfEMP1 protein

Olga Chesnokov,Jordan Merritt,Neta Milman,Sergey O Tcherniuk,Andrew V Oleinikov

doi:10.1038/s41598-018-36071-2

Abstract

Major complications and mortality from Plasmodium falciparum malaria are associated with cytoadhesion of parasite-infected erythrocytes (IE). The main parasite ligands for cytoadhesion are members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. Interactions of different host receptor-ligand pairs may lead to various pathological outcomes, like placental or cerebral malaria. It has been shown previously that IE can bind integrin αVβ3. Using bead-immobilized PfEMP1 constructs, we have identified that the PFL2665c DBLδ1_D4 domain binds to αVβ3 and αVβ6. A parasite line expressing PFL2665c binds to surface-immobilized αVβ3 and αVβ6; both are RGD motif-binding integrins. Interactions can be inhibited by cyloRGDFV peptide, an antagonist of RGD-binding integrins. This is a first, to the best of our knowledge, implication of a specific PfEMP1 domain for binding to integrins. These host receptors have important physiological functions in endothelial and immune cells; therefore, these results will contribute to future studies and a better understanding, at the molecular level, of the physiological outcome of interactions between IE and integrin receptors on the surface of host cells.

Highlights

Cytoadhesion of parasite-infected erythrocytes (IE) to endothelium and to immune cells plays a major role in complications and mortality from Plasmodium falciparum malaria[1]
Identification of novel host receptors that serve as ligands for IE is an important area of malaria studies
Recent examples include: a) identification of a novel interaction between EPCR and specific PfEMP1 domains and implication of this interaction in severe malaria[13], including potential importance of EPCR- and ICAM1-binding PfEMP1 domain tandem presence within the same protein for cerebral malaria[14]; b) discovery that another variable surface protein of P. falciparum, a member of the rifin family, interacts with leucocyte immunoglobulin-like receptor B1 and downregulates activation of immune cells[19]. These examples clearly demonstrate that our knowledge about host-parasite interactions is still limited and identification of novel receptor-domain pairs is essential for studies of malaria pathophysiology

Summary

Introduction

Cytoadhesion of parasite-infected erythrocytes (IE) to endothelium and to immune cells plays a major role in complications and mortality from Plasmodium falciparum malaria[1]. Our results (Fig. 1a) demonstrated that only DBLδ1_D4-CIDRβ1_D5 tandem from PFL2665c binds αVβ3 integrin.

Results

Conclusion