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Infection and Immunity, June 2009, p. 2530-2543, Vol. 77, No. 6
0019-9567/09/$08.00+0     doi:10.1128/IAI.00905-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Bacillus anthracis Edema Toxin Suppresses Human Macrophage Phagocytosis and Cytoskeletal Remodeling via the Protein Kinase A and Exchange Protein Activated by Cyclic AMP Pathways{triangledown}

Linsey A. Yeager,1* Ashok K. Chopra,1,2 and Johnny W. Peterson1,2

Department of Microbiology and Immunology,1 Center for Biodefense and Emerging Infectious Diseases and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas 775552

Received 22 July 2008/ Returned for modification 8 September 2008/ Accepted 14 March 2009

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 (M{Phi}) functions, such as phagocytosis, it was hypothesized that EdTx would exhibit similar suppressive activities. Our previous GeneChip data showed that EdTx downregulated M{Phi} 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 M{Phi} activity. Our data revealed that EdTx significantly suppressed human M{Phi} phagocytosis of Ames spores. Cytoskeletal changes, such as decreased cell spreading and lowered F-actin content, were also observed for toxin-treated M{Phi}s. 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 M{Phi} 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 M{Phi} phagocytosis and interfered with cytoskeletal remodeling.

* Corresponding author. Mailing address: 301 University Blvd., Galveston, TX 77555-0610. Phone: (409) 266-6824. Fax: (409) 747-6869. E-mail: layeager{at}utmb.edu

{triangledown} Published ahead of print on 23 March 2009.

Editor: S. R. Blanke

Infection and Immunity, June 2009, p. 2530-2543, Vol. 77, No. 6
0019-9567/09/$08.00+0     doi:10.1128/IAI.00905-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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