Bacillus anthracisEdema Toxin Suppresses Human Macrophage Phagocytosis and Cytoskeletal Remodeling via the Protein Kinase A and Exchange Protein Activated by Cyclic AMP Pathways
- 1 June 2009
- journal article
- Published by American Society for Microbiology in Infection and Immunity
- Vol. 77 (6), 2530-2543
- https://doi.org/10.1128/iai.00905-08
Abstract
Bacillus anthracis, the etiological agent of anthrax, is a gram-positive spore-forming bacterium. It produces edema toxin (EdTx), a powerful adenylate cyclase that increases cyclic AMP (cAMP) levels in host cells. Because other cAMP-increasing agents inhibit key macrophage (MΦ) functions, such as phagocytosis, it was hypothesized that EdTx would exhibit similar suppressive activities. Our previous GeneChip data showed that EdTx downregulated MΦ genes involved in actin cytoskeleton remodeling, including protein kinase A (PKA). To further examine the role of EdTx during anthrax pathogenesis, we explored the hypothesis that EdTx treatment leads to deregulation of the cAMP-dependent PKA system, resulting in impaired cytoskeletal functions essential for MΦ activity. Our data revealed that EdTx significantly suppressed human MΦ phagocytosis of Ames spores. Cytoskeletal changes, such as decreased cell spreading and lowered F-actin content, were also observed for toxin-treated MΦs. Further, EdTx altered the protein levels and activity of PKA and exchange protein activated by cAMP (Epac), a recently identified cAMP-binding molecule. By using PKA- and Epac-selective cAMP analogs, we confirmed the involvement of both pathways in the inhibition of MΦ functions elicited by EdTx-generated cAMP. These results suggested that EdTx weakened the host immune response by increasing cAMP levels, which then signaled via PKA and Epac to cripple MΦ phagocytosis and interfered with cytoskeletal remodeling.Keywords
This publication has 60 references indexed in Scilit:
- Human Monoclonal Antibody AVP-21D9 to Protective Antigen Reduces Dissemination of the Bacillus anthracis Ames Strain from the Lungs in a Rabbit ModelInfection and Immunity, 2007
- Bacillus anthracisSpores Stimulate Cytokine and Chemokine Innate Immune Responses in Human Alveolar Macrophages through Multiple Mitogen-Activated Protein Kinase PathwaysInfection and Immunity, 2006
- Direct binding of SWAP-70 to non-muscle actin is required for membrane rufflingJournal of Cell Science, 2006
- Direct Inhibition of T-Lymphocyte Activation by Anthrax Toxins In VivoInfection and Immunity, 2005
- Differentiation of human monocytic cell lines confers susceptibility to Bacillus anthracis lethal toxinCellular Microbiology, 2004
- Anthrax Edema Toxin Requires Influx of Calcium for Inducing Cyclic AMP Toxicity in Target CellsInfection and Immunity, 2002
- SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane rufflingNature, 2002
- Human Alveolar Macrophages and Granulocyte-macrophage Colony-stimulating Factor-induced Monocyte-derived Macrophages Are Resistant to H2O2 via Their High Basal and Inducible Levels of Catalase ActivityPublished by Elsevier BV ,2001
- AnthraxNew England Journal of Medicine, 1999
- Suppression of HIV Replication in Human Monocyte-Derived Macrophages Induced by Granulocyte/Macrophage Colony-Stimulating FactorAIDS Research and Human Retroviruses, 1995