Anaplasma phagocytophilum delays spontaneous human neutrophil apoptosis by modulation of multiple apoptotic pathways.
Anaplasma phagocytophilum infects human neutrophils and inhibits the intrinsic pathway of spontaneous neutrophil apoptosis by protecting mitochondrial membrane integrity. In the present study, we investigated the molecular signalling of the extrinsic pathway and the interaction between the intrinsic and extrinsic pathways in the inhibition of spontaneous human neutrophil apoptosis by A. phagocytophilum. Cell surface Fas clustering during spontaneous neutrophil apoptosis was significantly blocked by A. phagocytophilum infection. The cleavage of pro-caspase 8, caspase 8 activation and the cleavage of Bid, which links the intrinsic and extrinsic pathways, in the extrinsic pathway of spontaneous neutrophil apoptosis were inhibited by A. phagocytophilum infection. Inhibition of this pathway was active as the cleavage of pro-caspase 8 and Bid in anti-Fas-induced neutrophil apoptosis was also inhibited by A. phagocytophilum infection. Likewise, A. phagocytophilum infection inhibited the pro-apoptotic Bax translocation to mitochondria, activation of caspase 9, the initiator caspase in the intrinsic pathway, and the degradation of a potent caspase inhibitor, X-chromosome-linked inhibitor of apoptosis protein (XIAP), during spontaneous neutrophil apoptosis. These data point to a novel mechanism induced by A. phagocytophilum involving both extrinsic and intrinsic pathways to ensure to delay the apoptosis of host neutrophils.
Ge
Yan
Y
Department of Veterinary Biosciences, The Ohio State University, Columbus, 43210, USA.
Rikihisa
Yasuko
Y
D041081:Anaplasma phagocytophilum / Q000254:growth & development*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D005434:Flow Cytometry / Q000379:methods; D018922:HL-60 Cells; D006801:Humans; D007075:Immunoglobulin M / Q000494:pharmacology; D018613:Microscopy, Confocal / Q000379:methods; D008954:Models, Biological; D009504:Neutrophils / Q000166:cytology / Q000469:parasitology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism / Q000502:physiology
C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; D007075:Immunoglobulin M; D051636:X-Linked Inhibitor of Apoptosis Protein; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases