title: Downregulation of CXCL12 signaling and altered hematopoietic stem and progenitor cell trafficking in a murine model of acute Anaplasma phagocytophilum infection.
abstract: Infection with a variety of bacterial pathogens results in hematopoietic stem and progenitor cell (HSPC) mobilization. The mechanism and kinetics of HSPC mobilization during infection are largely unknown. Previously, we found altered HSPC activity in bone marrow, spleen and blood during infection with Anaplasma phagocytophilum, the agent of granulocytic anaplasmosis. We hypothesized that altered CXCL12/CXCR4 signaling, a central pathway for HSPC homing to, and retention within, the bone marrow, plays a role in infection-induced alterations in HSPC number and trafficking. Mice were infected with A. phagocytophilum. Lineage-cKit+ HSPCs were enumerated and proliferation determined. CXCL12 and CXCR4 mRNA were quantified along with CXCL12 protein, and CXCR4 surface, intracellular and total protein expression in HSPCs was determined. Increased bone marrow proliferation of HSPCs began at 2 d post-infection followed by HSPC mobilization and splenic homing. Proliferation of resident HSPCs contributed to increased splenic HSPC numbers. Bone marrow CXCL12 mRNA and protein levels were decreased at 4-8 d post-infection concurrent with HSPC mobilization. CXCR4 protein parameters were decreased in bone marrow HSPCs throughout 2-6 d post-infection. Reduction of CXCL12/CXCR4 signaling simultaneously occurs with HSPC mobilization from bone marrow. Findings suggest that deranged CXCL12/CXCR4 signaling plays a causal role in HSPC mobilization during acute A. phagocytophilum infection.
authors.affiliation: Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Johns
authors.forename: D L
authors.initials: DL
authors.lastname: Borjesson
mesh_terms: D000208:Acute Disease; D041081:Anaplasma phagocytophilum / Q000276:immunology*; D000711:Anaplasmataceae Infections / Q000276:immunology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D002454:Cell Differentiation; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D051379:Mice; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4