A Viral Nanoparticle with Dual Function as an Anthrax Antitoxin and Vaccine

Darly J Manayani,G Jonah A Rainey,Marianne Manchester,Heather M Scobie,Mark Yeager,Diane Thomas,Vijay Reddy,Anette Schneemann,Kelly A Dryden,Marc E Siladi,John A T Young,John M Marlett,Michael E Pique,Scott J Hultgren

doi:10.1371/journal.ppat.0030142

Abstract

The recent use of Bacillus anthracis as a bioweapon has stimulated the search for novel antitoxins and vaccines that act rapidly and with minimal adverse effects. B. anthracis produces an AB-type toxin composed of the receptor-binding moiety protective antigen (PA) and the enzymatic moieties edema factor and lethal factor. PA is a key target for both antitoxin and vaccine development. We used the icosahedral insect virus Flock House virus as a platform to display 180 copies of the high affinity, PA-binding von Willebrand A domain of the ANTXR2 cellular receptor. The chimeric virus-like particles (VLPs) correctly displayed the receptor von Willebrand A domain on their surface and inhibited lethal toxin action in in vitro and in vivo models of anthrax intoxication. Moreover, VLPs complexed with PA elicited a potent toxin-neutralizing antibody response that protected rats from anthrax lethal toxin challenge after a single immunization without adjuvant. This recombinant VLP platform represents a novel and highly effective, dually-acting reagent for treatment and protection against anthrax.

Highlights

Anthrax is caused by the spore-forming, Gram-positive bacterium Bacillus anthracis [1]
The toxic effects of B. anthracis are predominantly due to an AB-type toxin made up of the receptor-binding subunit protective antigen (PA) and two enzymatic subunits called lethal factor and edema factor
Protective immunity to B. anthracis infection is conferred by antibodies against PA, which is the primary component of the current anthrax vaccine

Summary

Introduction

Anthrax is caused by the spore-forming, Gram-positive bacterium Bacillus anthracis [1]. Disease symptoms are initially nonspecific and systemic dissemination of anthrax toxin can occur prior to antibiotic treatment [2]. Widely distributed on human cells, have been identified: anthrax toxin receptor/tumor endothelial marker 8 (ANTXR1) [7] and capillary morphogenesis gene 2 (ANTXR2) [8]. Both receptors bind PA through a 200–amino acid extracellular von Willebrand factor A (VWA) domain, the VWA domain of ANTXR2 has a 1,000-fold higher binding affinity for PA than the VWA domain of ANTXR1. The lowdensity lipoprotein receptor-related protein LRP6 was shown to function as a co-receptor for anthrax toxin internalization, this finding is controversial [12,13]

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Conclusion