Toxin-neutralizing antibodies elicited by naturally acquired cutaneous anthrax are elevated following severe disease and appear to target conformational epitopes.

Eric K Dumas,Mehmet Doganay,Emily Muns,Jason Larabee,Uner Kayabas,Hayati Demiraslan,Rebecca M Sparks,A Darise Farris,Adriana Zamora,Geert-Jan Boons,Rebecca J Ingram,Lori Garman,Judith A James,Jimmy D Ballard

doi:10.1371/journal.pone.0230782

Abstract

Understanding immune responses to native antigens in response to natural infections can lead to improved approaches to vaccination. This study sought to characterize the humoral immune response to anthrax toxin components, capsule and spore antigens in individuals (n = 46) from the Kayseri and Malatya regions of Turkey who had recovered from mild or severe forms of cutaneous anthrax infection, compared to regional healthy controls (n = 20). IgG antibodies to each toxin component, the poly-γ-D-glutamic acid capsule, the Bacillus collagen-like protein of anthracis (BclA) spore antigen, and the spore carbohydrate anthrose, were detected in the cases, with anthrax toxin neutralization and responses to Protective Antigen (PA) and Lethal Factor (LF) being higher following severe forms of the disease. Significant correlative relationships among responses to PA, LF, Edema Factor (EF) and capsule were observed among the cases. Though some regional control sera exhibited binding to a subset of the tested antigens, these samples did not neutralize anthrax toxins and lacked correlative relationships among antigen binding specificities observed in the cases. Comparison of serum binding to overlapping decapeptides covering the entire length of PA, LF and EF proteins in 26 cases compared to 8 regional controls revealed that anthrax toxin-neutralizing antibody responses elicited following natural cutaneous anthrax infection are directed to conformational epitopes. These studies support the concept of vaccination approaches that preserve conformational epitopes.

Highlights

Bacillus anthracis is a Gram-positive, spore-forming bacterium that is the causative agent of anthrax infection
Cutaneous anthrax was diagnosed in the patients (n = 46) by history of contact with ill animals or contaminated animal products and the presence of one or more lesions
The site of the lesion or lesions for all patients was on the upper body, most often located on the finger, wrist or arm and less commonly on the face or neck

Summary

Introduction

Bacillus anthracis is a Gram-positive, spore-forming bacterium that is the causative agent of anthrax infection. While anthrax is naturally a disease of animals, humans can be incidentally infected. Human infection occurs through contact with B. anthracis spores, commonly through the handling of contaminated animal materials. Infection in humans can occur through the deliberate release of spores as a biological weapon, as was evidenced in the United States (US) in 2001 [1, 2]. There are currently four main classifications of anthrax based on the route of infection: cutaneous anthrax, gastrointestinal anthrax, inhalational anthrax, and injectional anthrax [3]. Cutaneous anthrax is initiated when B. anthracis spores penetrate the skin, often through a cut or abrasion. While 95% of anthrax cases worldwide are cutaneous, this classification has the lowest mortality rate, ranging from 10 to 40% without treatment to

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