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Vol. 19, Issue 4, 1427-1438, April 2008

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Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins

Division of Cell Biology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112-0565

Submitted July 5, 2007; Revised November 1, 2007; Accepted January 23, 2008
Monitoring Editor: John York

Uropathogenic Escherichia coli (UPEC) are the major cause of urinary tract infections (UTIs), and they have the capacity to induce the death and exfoliation of target uroepithelial cells. This process can be facilitated by the pore-forming toxin -hemolysin (HlyA), which is expressed and secreted by many UPEC isolates. Here, we demonstrate that HlyA can potently inhibit activation of Akt (protein kinase B), a key regulator of host cell survival, inflammatory responses, proliferation, and metabolism. HlyA ablates Akt activation via an extracellular calcium-dependent, potassium-independent process requiring HlyA insertion into the host plasma membrane and subsequent pore formation. Inhibitor studies indicate that Akt inactivation by HlyA involves aberrant stimulation of host protein phosphatases. We found that two other bacterial pore-forming toxins (aerolysin from Aeromonas species and -toxin from Staphylococcus aureus) can also markedly attenuate Akt activation in a dose-dependent manner. These data suggest a novel mechanism by which sublytic concentrations of HlyA and other pore-forming toxins can modulate host cell survival and inflammatory pathways during the course of a bacterial infection.

Address correspondence to: Matthew A. Mulvey (mulvey{at}path.utah.edu)

Abbreviations used: CNF1, cytotoxic necrotizing factor 1; EGF, epidermal growth factor; LPS, lipopolysaccharide; MOI, multiplicity of infection; PKB, protein kinase B; PMB, polymyxin B; PtdIns, phosphatidylinositol; TNF, tumor necrosis factor; UPEC, uropathogenic E. coli; UTI, urinary tract infection.

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