Molecular Camouflage of Plasmodium falciparum Merozoites by Binding of Host Vitronectin to P47 Fragment of SERA5

Takahiro Tougan,Miki Shinohara,Toshihiro Horii,Takafumi Tsuboi,Masayuki Morita,Akira Shinohara,Jyotheeswara R Edula,Eizo Takashima

doi:10.1038/s41598-018-23194-9

Takahiro Tougan, Miki Shinohara + Show 6 more

Open Access

https://doi.org/10.1038/s41598-018-23194-9

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Abstract

The malaria parasite Plasmodium falciparum proliferates in the blood stream where the host immune system is most active. To escape from host immunity, P. falciparum has developed a number of evasion mechanisms. Serine repeat antigen 5 (SERA5) is a blood stage antigen highly expressed at late trophozoite and schizont stages. The P47 N-terminal domain of SERA5, the basis of SE36 antigen of the blood stage vaccine candidate under clinical trials, covers the merozoite surface. Exploring the role of the P47 domain, screening of serum proteins showed that vitronectin (VTN) directly binds to 20 residues in the C-terminal region of SE36. VTN co-localized with P47 domain in the schizont and merozoite stages. Phagocytosis assay using THP-1 cells demonstrated that VTN bound to SE36 prevented engulfment of SE36-beads. In addition, several serum proteins localized on the merozoite surface, suggesting that host proteins camouflage merozoites against host immunity via binding to VTN.

Highlights

Serine repeat antigen 5 (SERA5)[7] is an abundant blood stage antigen highly expressed at late trophozoite and schizont stages as a 120-kDa precursor and secreted into the lumen of the parasitophorous vacuole of infected red blood cells after removal of the signal peptide
To see whether P47 fragment could bind to the bulk of serum proteins, we conducted ELISA-based binding assay using SE36, a recombinant form of P47 domain
The assay between SE36 and total serum protein in naïve human serum (NHS) with double reciprocal dilutions suggested that SE36 binds to serum protein(s) (Supplementary Fig. 1)

Summary

Introduction

Serine repeat antigen 5 (SERA5)[7] is an abundant blood stage antigen highly expressed at late trophozoite and schizont stages as a 120-kDa precursor and secreted into the lumen of the parasitophorous vacuole of infected red blood cells (iRBCs) after removal of the signal peptide. P47 and P18 fragments form a 65-kDa complex by disulfide bonding, and associates with the merozoite surface, suggesting that these fragments are exposed to human serum[9,12]. Recombinant proteins made from P47 domain has been shown to be immunogenic in the field and induced antibodies inhibited in vitro and in animal models erythrocyte invasion and parasite replication[13] (for review, ref.[14]). In vitro studies demonstrated that antibodies against the P47 domain showed antiparasitic effects such as complement-mediated cell lysis of segmented schizont[17] or merozoite agglutination[18]. The RGD motif enhances monocyte-induced phagocytosis of apoptotic target cells opsonized with IgG or complement C3b24,25. Serum proteins that bind to VTN covers the merozoite surface

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