Association of antibodies to Plasmodium falciparum reticulocyte binding protein homolog 5 with protection from clinical malaria.

Chris Y H Chiu,Ivo Mueller,Jennifer K Thompson,Louis Schofield,Julie Healer,Arjun Raghuwanshi,Lin Chen,Connie S N Li Wai Suen,Diana S Hansen,Aiki Kaul,Laxman Savergave,Alan F Cowman,Peter M Siba

doi:10.3389/fmicb.2014.00314

Abstract

Emerging evidence suggests that antibodies against merozoite proteins involved in Plasmodium falciparum invasion into the red blood cell (RBC) play an important role in clinical immunity to malaria. The protein family of parasite antigens known as P. falciparum reticulocyte binding protein-like homolog (PfRh) is required for RBC invasion. PfRh5 is the only member within the PfRh family that cannot be genetically deleted, suggesting it plays an essential role in parasite survival. This antigen forms a complex with the cysteine-rich P. falciparum Rh5 interacting protein (PfRipr), on the merozoite surface during RBC invasion. The PfRh5 ectodomain sequence and a C-terminal fragment of PfRipr were cloned and expressed in Escherichia coli and baculovirus-infected cells, respectively. Immunization of rabbits with these recombinant proteins induced antibodies able to inhibit growth of various P. falciparum strains. Antibody responses to these proteins were investigated in a treatment–re-infection study conducted in an endemic area of Papua New Guinea (PNG) to determine their contribution to naturally acquired immunity. Antibody titers to PfRh5 but not PfRipr showed strong association with protection against P. falciparum clinical episodes. When associations with time-to-first infection were analyzed, high antibody levels against PfRh5 were also found to be associated with protection from high-density infections but not from re-infection. Together these results indicate that PfRh5 is an important target of protective immunity and constitutes a promising vaccine candidate.

Highlights

Malaria is one of the most serious infectious diseases of humans causing 500 million clinical cases annually, with nearly 25% of the global burden occurring in the Asia-Pacific
Over the past 10 years, a large body of data has been generated towards understanding the molecular basis of merozoite invasion into the erythrocyte and many parasite antigens have been characterized
PfRh5 has been identified as an attractive vaccine candidate since it appears to be essential for parasite survival (Baum et al, 2009), has limited sequence polymorphisms and upon animal immunization induces broadly growth inhibitory antibodies (Douglas et al, 2011; Bustamante et al, 2013; Reddy et al, 2014)

Summary

Introduction

Malaria is one of the most serious infectious diseases of humans causing 500 million clinical cases annually, with nearly 25% of the global burden occurring in the Asia-Pacific. The blood stage of the Plasmodium parasite is entirely responsible for malariaassociated pathology (Miller et al, 2002). After years of repeated exposure, individuals living in endemic areas develop clinical immunity. This form of protection does not result in sterilizing immunity but prevents clinical episodes by significantly reducing parasite burden. Acquired immunity predominantly targets blood-stage parasites and appears to require antibody responses since passive transfer of sera from clinically immune individuals protects nonimmune recipients from high parasitemia and disease symptoms (Cohen et al, 1961)

Methods

Results

Conclusion