Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes

Vineet I Patel,Brent R Brown,Jordan P Metcalf,J Leland Booth,Mikhail Dozmorov

doi:10.3390/toxins12070464

Vineet I Patel, Brent R Brown + Show 3 more

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https://doi.org/10.3390/toxins12070464

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Abstract

Bacillus anthracis, the causative agent of inhalation anthrax, is a serious concern as a bioterrorism weapon. The vegetative form produces two exotoxins: Lethal toxin (LT) and edema toxin (ET). We recently characterized and compared six human airway and alveolar-resident phagocyte (AARP) subsets at the transcriptional and functional levels. In this study, we examined the effects of LT and ET on these subsets and human leukocytes. AARPs and leukocytes do not express high levels of the toxin receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2). Less than 20% expressed surface TEM8, while less than 15% expressed CMG2. All cell types bound or internalized protective antigen, the common component of the two toxins, in a dose-dependent manner. Most protective antigen was likely internalized via macropinocytosis. Cells were not sensitive to LT-induced apoptosis or necrosis at concentrations up to 1000 ng/mL. However, toxin exposure inhibited B. anthracis spore internalization. This inhibition was driven primarily by ET in AARPs and LT in leukocytes. These results support a model of inhalation anthrax in which spores germinate and produce toxins. ET inhibits pathogen phagocytosis by AARPs, allowing alveolar escape. In late-stage disease, LT inhibits phagocytosis by leukocytes, allowing bacterial replication in the bloodstream.

Highlights

Bacillus anthracis is a Gram positive, spore-forming, rod-shaped, and facultatively anaerobic bacterial species
Binding across all exposure levels. These results suggest that protective antigen (PA) can bind and/or be internalized by human alveolar-resident phagocyte (AARP) and leukocytes via one or more mechanisms that are independent of tumor endothelium marker-8 (TEM8) and
Our study examined the effects of anthrax Lethal toxin (LT) and edema toxin (ET) on human phagocytic subsets in the lung

Summary

Introduction

Bacillus anthracis is a Gram positive, spore-forming, rod-shaped, and facultatively anaerobic bacterial species. B. anthracis is the causative agent of the disease anthrax, with three forms of the disease occurring depending on the portal of entry of dormant bacterial spores [1]. Inhalation anthrax in humans has a mortality rate greater than 90% if not diagnosed and treated early [1]. This high fatality rate, along with the ease of dissemination of B. anthracis spores, has led to this organism being classified as a category A bioterrorism agent (https://www.selectagents.gov/). Events, such as the 2001 letter attacks in the United

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