title: Anaplasma phagocytophilum causes global induction of antiapoptosis in human neutrophils.
abstract: Anaplasma phagocytophilum (Ap), the agent of the tick-borne disease human granulocytic anaplasmosis, is an obligate intracellular pathogen unique in its ability to target and replicate within neutrophils. It profoundly inhibits neutrophil apoptosis, prolonging neutrophil survival from hours to days. To determine the basis of antiapoptosis, we compared gene expression in Ap-infected vs mock-infected human neutrophils. Antiapoptosis genes were consistently and significantly up-regulated (2- to 15-fold) within 1-3 h. These genes synergistically inhibit apoptosis through several interconnected pathways, including p38MAPK (MAP2K3), ERK (IER3), PI3K (PRKCD), and NF-kappaB (BCL2A1, NFKB1, NFKBIA, GADD45B). Both extrinsic death receptor (TNFAIP3, CFLAR, SOD2) and intrinsic mitochondrial (BCL2A1, PIM2, BIRC3) pathways were affected as confirmed by reductions in both caspase 3 and caspase 8 activities. Several important antiapoptotic genes noted to be up-regulated in Ap-infected neutrophils were not up-regulated during Ap infection of HL-60 cells (which is not antiapoptotic). In conclusion, just as apoptosis may be triggered through multiple molecular pathways, effective antiapoptosis of neutrophils is achieved rapidly and redundantly by this intracellular pathogen dependent on cell survival.
authors.affiliation: Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
authors.forename: Hin C
authors.initials: HC
authors.lastname: Lee
authors.forename: Jesse L
authors.initials: JL
authors.lastname: Goodman
mesh_terms: D041081:Anaplasma phagocytophilum / Q000472:pathogenicity*; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D016873:Ehrlichiosis / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D005786:Gene Expression Regulation; D018922:HL-60 Cells; D006801:Humans; D009504:Neutrophils / Q000382:microbiology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D015854:Up-Regulation