title: Infection with Anaplasma phagocytophilum activates the phosphatidylinositol 3-Kinase/Akt and NF-κB survival pathways in neutrophil granulocytes.
abstract: Anaplasma phagocytophilum, a Gram-negative, obligate intracellular bacterium infects primarily neutrophil granulocytes. Infection with A. phagocytophilum leads to inhibition of neutrophil apoptosis and consequently contributes to the longevity of the host cells. Previous studies demonstrated that the infection inhibits the executionary apoptotic machinery in neutrophils. However, little attempt has been made to explore which survival signals are modulated by the pathogen. The aim of the present study was to clarify whether the phosphatidylinositol 3-kinase (PI3K)/Akt and NF-κB signaling pathways, which are considered as important survival pathways in neutrophils, are involved in A. phagocytophilum-induced apoptosis delay. Our data show that infection of neutrophils with A. phagocytophilum activates the PI3K/Akt pathway and suggest that this pathway, which in turn maintains the expression of the antiapoptotic protein Mcl-1, contributes to the infection-induced apoptosis delay. In addition, the PI3K/Akt pathway is involved in the activation of NF-κB in A. phagocytophilum-infected neutrophils. Activation of NF-κB leads to the release of interleukin-8 (IL-8) from infected neutrophils, which, in an autocrine manner, delays neutrophil apoptosis. In addition, enhanced expression of the antiapoptotic protein cIAP2 was observed in A. phagocytophilum-infected neutrophils. Taken together, the data indicate that upstream of the apoptotic cascade, signaling via the PI3K/Akt pathway plays a major role for apoptosis delay in A. phagocytophilum-infected neutrophils.
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany.
authors.forename: Arup
authors.initials: A
authors.lastname: Sarkar
authors.forename: Lars
authors.initials: L
authors.lastname: Hellberg
authors.forename: Asima
authors.initials: A
authors.lastname: Bhattacharyya
authors.forename: Martina
authors.initials: M
authors.lastname: Behnen
authors.forename: Keqing
authors.initials: K
authors.lastname: Wang
authors.forename: Janet M
authors.initials: JM
authors.lastname: Lord
authors.forename: Sonja
authors.initials: S
authors.lastname: Möller
authors.forename: Maja
authors.initials: M
authors.lastname: Kohler
authors.forename: Werner
authors.initials: W
authors.lastname: Solbach
authors.forename: Tamás
authors.initials: T
authors.lastname: Laskay
mesh_terms: D041081:Anaplasma phagocytophilum / Q000378:metabolism / Q000472:pathogenicity*; D017209:Apoptosis; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002478:Cells, Cultured; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D010587:Phagocytosis; D058539:Phosphatidylinositol 3-Kinase / Q000096:biosynthesis / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D016209:Interleukin-8; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt