Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes
<i>Bacillus anthracis</i>, 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...
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MDPI AG
2020-07-01
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| Series: | Toxins |
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| Online Access: | https://www.mdpi.com/2072-6651/12/7/464 |
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| author | Vineet I. Patel J. Leland Booth Mikhail Dozmorov Brent R. Brown Jordan P. Metcalf |
| author_facet | Vineet I. Patel J. Leland Booth Mikhail Dozmorov Brent R. Brown Jordan P. Metcalf |
| author_sort | Vineet I. Patel |
| collection | DOAJ |
| description | <i>Bacillus anthracis</i>, 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 <i>B. anthracis</i> 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. |
| first_indexed | 2024-03-10T18:20:53Z |
| format | Article |
| id | doaj.art-773d7781e1b642bd998dd58369a0f33f |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-03-10T18:20:53Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-773d7781e1b642bd998dd58369a0f33f2023-11-20T07:20:08ZengMDPI AGToxins2072-66512020-07-0112746410.3390/toxins12070464Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood PhagocytesVineet I. Patel0J. Leland Booth1Mikhail Dozmorov2Brent R. Brown3Jordan P. Metcalf4Department of Medicine, Pulmonary, Critical Care & Sleep Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USADepartment of Medicine, Pulmonary, Critical Care & Sleep Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USADepartment of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USADepartment of Medicine, Pulmonary, Critical Care & Sleep Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USADepartment of Medicine, Pulmonary, Critical Care & Sleep Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA<i>Bacillus anthracis</i>, 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 <i>B. anthracis</i> 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.https://www.mdpi.com/2072-6651/12/7/464anthraxlethal toxinedema toxinsporespathogenesishuman lung |
| spellingShingle | Vineet I. Patel J. Leland Booth Mikhail Dozmorov Brent R. Brown Jordan P. Metcalf Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes Toxins anthrax lethal toxin edema toxin spores pathogenesis human lung |
| title | Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes |
| title_full | Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes |
| title_fullStr | Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes |
| title_full_unstemmed | Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes |
| title_short | Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes |
| title_sort | anthrax edema and lethal toxins differentially target human lung and blood phagocytes |
| topic | anthrax lethal toxin edema toxin spores pathogenesis human lung |
| url | https://www.mdpi.com/2072-6651/12/7/464 |
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