Bacteria differentially induce degradation of Bcl-x(L), a survival protein, by human platelets

Kraemer, BF; Campbell, RA; Schwertz, H; Franks, ZG; de Abreu, AV; Grundler, K; Kile, BT; Dhakal, BK; Rondina, MT; Kahr, WHA; Mulvey, MA; Blaylock, RC; Zimmerman, GA; Weyrich, AS

Author(s): Kraemer, BF; Campbell, RA; Schwertz, H; Franks, ZG; de Abreu, AV; Grundler, K; Kile, BT; Dhakal, BK; Rondina, MT; Kahr, WHA; Mulvey, MA; Blaylock, RC; Zimmerman, GA; Weyrich, AS;
Details: Publication Year 2012-12-13,Volume 120,Issue #25,Page 5014-5020
Journal Title: BLOOD
Publication Type: Journal Article
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-x(L), 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 alpha-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 alpha-hemolysin. Like alpha-hemolysin, purified alpha-toxin readily degrades Bcl-xL protein in platelets, as do clinical Staphylococcus aureus isolates that produce alpha-toxin. Inhibition of calpain activity, but not the proteasome, rescues Bcl-xL protein degradation in platelets coincubated with pathogenic E coli including alpha-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. (Blood. 2012; 120(25): 5014-5020)
Publisher: AMER SOC HEMATOLOGY
Research Division(s): Cancer And Haematology
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525025/
Publisher's Version: https://doi.org/10.1182/blood-2012-04-420661

Creation Date: 2012-12-13 12:00:00