Passive Immunotherapy Protects against Enteric Invasion and Lethal Sepsis in a Murine Model of Gastrointestinal Anthrax.

Bruce Huang,Hui Fang,David Frucht,David Rotstein,Tao Xie

doi:10.3390/toxins7103960

Abstract

The principal portal for anthrax infection in natural animal outbreaks is the digestive tract. Enteric exposure to anthrax, which is difficult to detect or prevent in a timely manner, could be exploited as an act of terror through contamination of human or animal food. Our group has developed a novel animal model of gastrointestinal (GI) anthrax for evaluation of disease pathogenesis and experimental therapeutics, utilizing vegetative Bacillus anthracis (Sterne strain) administered to A/J mice (a complement-deficient strain) by oral gavage. We hypothesized that a humanized recombinant monoclonal antibody (mAb) * that neutralizes the protective antigen (PA) component of B. anthracis lethal toxin (LT) and edema toxin (ET) could be an effective treatment. Although the efficacy of this anti-anthrax PA mAb has been shown in animal models of inhalational anthrax, its activity in GI infection had not yet been ascertained. We hereby demonstrate that passive immunotherapy with anti-anthrax PA mAb, administered at the same time as gastrointestinal exposure to B. anthracis, prevents lethal sepsis in nearly all cases (>90%), while a delay of up to forty-eight hours in treatment still greatly reduces mortality following exposure (65%). Moreover, passive immunotherapy protects against enteric invasion, associated mucosal injury and subsequent dissemination by gastrointestinal B. anthracis, indicating that it acts to prevent the initial stages of infection. * Expired raxibacumab being cycled off the Strategic National Stockpile; biological activity confirmed by in vitro assay.

Highlights

Incidental cutaneous or inhalational human infections with Bacillus anthracis (Gram-positive spore-forming aerobic or facultative anaerobic bacteria) have intermittently occurred in agricultural regions for millennia, largely due to direct exposures associated with the husbandry, consumption or pelt preparation of domesticated ruminant herbivores [1]
Justifiably intense scientific attention was subsequently directed toward investigating the mechanisms of inhalational anthrax infections [4,5,6], it is generally regarded that the principal route of infection for B. anthracis in natural settings is by means of enteric entry [7]
A/J mice were administered a lethal dose of vegetative Bacillus anthracis (Sterne) bacteria by oral gavage; intravenous treatment with a single dose of anti-protective antigen (PA) monoclonal antibody (mAb) (40 mg/kg) or saline control was administered either concurrently or two days later

Summary

Introduction

Incidental cutaneous or inhalational human infections with Bacillus anthracis (Gram-positive spore-forming aerobic or facultative anaerobic bacteria) have intermittently occurred in agricultural regions for millennia, largely due to direct exposures associated with the husbandry, consumption or pelt preparation of domesticated ruminant herbivores [1]. Justifiably intense scientific attention was subsequently directed toward investigating the mechanisms of inhalational anthrax infections [4,5,6], it is generally regarded that the principal route of infection for B. anthracis in natural settings is by means of enteric entry [7]. This avenue may be the route most favorable to its growth and propagation in grazing ruminant wildlife and livestock animals [7,8]. Understanding disease pathogenesis and treatment modalities in the setting of gastrointestinal anthrax is a worthwhile objective

Results

Discussion

Conclusion