title: Bacteria differentially induce degradation of Bcl-xL, a survival protein, by human platelets.
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-x(L) protein in platelets. Bcl-x(L) 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-x(L) protein in platelets, as do clinical Staphylococcus aureus isolates that produce α-toxin. Inhibition of calpain activity, but not the proteasome, rescues Bcl-x(L) 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.
authors.affiliation: The Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Bjoern F
authors.initials: BF
authors.lastname: Kraemer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Campbell
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schwertz
authors.forename: Zechariah G
authors.initials: ZG
authors.lastname: Franks
authors.forename: Adriana
authors.initials: A
authors.lastname: Vieira de Abreu
authors.forename: Katharina
authors.initials: K
authors.lastname: Grundler
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.forename: Bijaya K
authors.initials: BK
authors.lastname: Dhakal
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Rondina
authors.forename: Walter H A
authors.initials: WH
authors.lastname: Kahr
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Mulvey
authors.forename: Robert C
authors.initials: RC
authors.lastname: Blaylock
authors.forename: Guy A
authors.initials: GA
authors.lastname: Zimmerman
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Weyrich
mesh_terms: D017209:Apoptosis; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism / Q000382:microbiology*; D002154:Calpain / Q000378:metabolism; D004926:Escherichia coli / Q000502:physiology*; D004927:Escherichia coli Infections / Q000382:microbiology; D054884:Host-Pathogen Interactions; D006801:Humans; D059748:Proteolysis; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000502:physiology*; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: D051020:bcl-X Protein; D002154:Calpain