Bacteria differentially induce degradation of Bcl-xL, a survival protein, by human platelets

Bjoern F. Kraemer, Robert A. Campbell, Hansjorg Schwertz, Zechariah G. Franks, Adriana Vieira de Abreu, Katharina Grundler, Benjamin T. Kile, Bijaya K. Dhakal, Matthew T. Rondina, Walter H. A. Kahr, Matthew A. Mulvey, Robert C. Blaylock, Guy A. Zimmerman, Andrew S. Weyrich

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40 Citations (Scopus)

Abstract

Bacteria can enter the bloodstream in response to infectious insults. Bacteremia elicits several immune and clinical complications, including thrombocytopenia. A primary cause of thrombocytopenia is shortened survival of platelets. We demonstrate that pathogenic bacteria induce apoptotic events in platelets that include calpain-mediated degradation of Bcl-xL, an essential regulator of platelet survival. Specifically, bloodstream bacterial isolates from patients with sepsis induce lateral condensation of actin, impair mitochondrial membrane potential, and degrade Bcl-xL protein in platelets. Bcl-xL protein degradation is enhanced when platelets are exposed to pathogenic Escherichia coli that produce the pore-forming toxin α-hemolysin, a response that is markedly attenuated when the gene is deleted from E coli. We also found that nonpathogenic E coli gain degrading activity when they are forced to express α-hemolysin. Like α-hemolysin, purified α-toxin readily degrades Bcl-xL protein in platelets, as do clinical Staphylococcus aureus isolates that produce α-toxin. Inhibition of calpain activity, but not the proteasome, rescues Bcl-xL protein degradation in platelets coincubated with pathogenic E coli including α-hemolysin producing strains. This is the first evidence that pathogenic bacteria can trigger activation of the platelet intrinsic apoptosis program and our results suggest a new mechanism by which bacterial pathogens might cause thrombocytopenia in patients with bloodstream infections.

Original languageEnglish
Pages (from-to)5014-5020
Number of pages7
JournalBlood
Volume120
Issue number25
DOIs
Publication statusPublished - 13 Dec 2012
Externally publishedYes

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