Targeting the Conserved Fusion Loop of HAP2 Inhibits the Transmission of Plasmodium berghei and falciparum

Fiona Angrisano,Katarzyna A Sala,Dari F Da,Yanjie Liu,Jimin Pei,Nick V Grishin,William J Snell,Andrew M Blagborough

doi:10.1016/j.celrep.2017.11.024

Abstract

SummaryInhibiting transmission of Plasmodium is a central strategy in malarial eradication, and the biological process of gamete fusion during fertilization is a proven target for this approach. The lack of a structure or known molecular function of current anti-malarial vaccine targets has previously been a hindrance in the development of transmission-blocking vaccines. Structure/function studies have indicated that the conserved gamete membrane fusion protein HAP2 is a class II viral fusion protein. Here, we demonstrate that targeting a function-critical site of the fusion/cd loop with species-specific antibodies reduces Plasmodium berghei transmission in vivo by 58.9% and in vitro fertilization by up to 89.9%. A corresponding reduction in P. falciparum transmission (75.5%/36.4% reductions in intensity/prevalence) is observed in complimentary field studies. These results emphasize conserved mechanisms of fusion in Apicomplexa, while highlighting an approach to design future anti-malarial transmission-blocking vaccines.

Highlights

Malaria remains one of the most prevalent tropical infectious diseases with an estimated 212 million new cases and 429,000 deaths annually (World Health Organization, 2016)
Successful transmission of Plasmodium from humans to mosquitoes is dependent on the presence of sexually committed gametocytes in the peripheral blood, which rapidly undergo the process of activation and differentiate into male and female gametes upon uptake by the Anopheline vector within a blood meal
Analysis of HAP2 Primary Sequence in Plasmodium Recent bioinformatic and structural analysis of C. reinhardtii HAP2 identified similarities to eukaryotic/viral class II fusion proteins, revealing a specific segment 42-residue region within a cysteine-rich portion of HAP2 that corresponded to the predicted fusion loop (Fedry et al, 2017)

Summary

Introduction

Malaria remains one of the most prevalent tropical infectious diseases with an estimated 212 million new cases and 429,000 deaths annually (World Health Organization, 2016). Gamete fusion during fertilization is an essential step in the Plasmodium life cycle. In Plasmodium, only three proteins have been discovered that have a demonstrable role in the mutual recognition of gametes; P48/45, P47, and P230 (van Dijk et al, 2001, 2010; van Schaijk et al, 2006). This initial recognition/adhesion step is postulated to initiate a signal transduction cascade that activates the microgamete and exposes new, fusogenic regions of the sperm plasma membrane (Liu et al, 2008). Despite the obvious biological importance of fertilization and its proven previous targeting as a potential point to disrupt the parasitic life cycle with therapeutics (Carter, 2001; van Dijk et al, 2010; Blagborough et al, 2013a), our knowledge of the cellular and molecular mechanisms underlying gamete fusion in Plasmodium is surprisingly sparse

Results

Discussion

Conclusion