A Novel Toll-Like Receptor 2 Agonist Protects Mice in a Prophylactic Treatment Model Against Challenge With Bacillus anthracis.

Chih-Yuan Chiang,Ugo D’Oro,Tom Wu,Douglas J Lane,Janice Hampton,Sina Bavari,Bishnu P Nayak,Jianfeng Pan,Yefen Zou,Tim Hoffman,Rekha G Panchal,Nicholas Valiante,Andrew T Miller,Jillian Maginnis,Michael Cooke

doi:10.3389/fmicb.2022.803041

Abstract

Current therapies for anthrax include the use of antibiotics (i.e., doxycycline, and ciprofloxacin), an anthrax vaccine (BioThrax) and Bacillus anthracis-specific, monoclonal antibody (mAb) (i.e., Raxibacumab and obiltoxaximab). In this study, we investigated the activity of immunomodulators, which potentiate inflammatory responses through innate immune receptors. The rationale for the use of innate immune receptor agonists as adjunctive immunomodulators for infectious diseases is based on the concept that augmentation of host defense should promote the antimicrobial mechanism of the host. Our aim was to explore the anti-B. anthracis effector function of Toll-like receptor (TLR) agonists using a mouse model. Amongst the six TLR ligands tested, Pam3CSK4 (TLR1/2 ligand) was the best at protecting mice from lethal challenge of B. anthracis. We then evaluated the activity of a novel TLR2 ligand, DA-98-WW07. DA-98-WW07 demonstrated enhanced protection in B. anthracis infected mice. The surviving mice that received DA-98-WW07 when re-challenged with B. anthracis 20 days post the first infection showed increased survival rate. Moreover, ciprofloxacin, when treated in adjunct with a suboptimal concentration of DA-98-WW07 demonstrated augmented activity in protecting mice from B. anthracis infection. Taken together, we report the prophylactic treatment potential of DA-98-WW07 for anthrax and the utility of immunomodulators in combination with an antibiotic to treat infections caused by the B. anthracis bacterium.

Highlights

Bacillus anthracis, the etiological agent of anthrax, is rod-shaped, gram-positive, and nonmotile bacterium
Each of the synthetic Toll-like receptor (TLR) agonists that were used in the study had reported concentration at which maximal cytokine secretion is stimulated from dendritic cells (Aliprantis et al, 1999; Krug et al, 2001; Lee et al, 2003; Yamamoto et al, 2003; Buwitt-Beckmann et al, 2005)
The results suggest that potentiating the host immune response by agonizing TLR2 protected mice from lethal infection of B. anthracis

Summary

Introduction

The etiological agent of anthrax, is rod-shaped, gram-positive, and nonmotile bacterium. B. anthracis exists in either vegetative or spore forms. The vegetative form of B. anthracis rarely causes diseases. The spore form of B. anthracis is infectious and highly resistant to inactivation. The spores can remain dormant in the environment for decades and infect grazing animals that ingest the spores. B. anthracis spores can be introduced into the host through ingestion, skin lesion and inhalation. Humans can TLR2 Agonist Protects Against B. anthracis acquire the disease following exposure to spores released purposely as a bioterrorist weapon or accidentally from naturally occurring sources. Given that inhalational anthrax is deadly, B. anthracis is ranked near the top of the list for potential bio-threat agents

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