title: Anaplasma phagocytophilum-infected neutrophils enhance transmigration of Borrelia burgdorferi across the human blood brain barrier in vitro.
abstract: The manifestations of Lyme disease, caused by Ixodes spp. tick-transmitted Borrelia burgdorferi, range from skin infection to bloodstream invasion into the heart, joints and nervous system. The febrile infection human granulocytic anaplasmosis is caused by a neutrophilic rickettsia called Anaplasma phagocytophilum, also transmitted by Ixodes ticks. Previous studies suggest that co-infection with A. phagocytophilum contributes to increased spirochetal loads and severity of Lyme disease. However, a common link between these tick-transmitted pathogens is dissemination into blood or tissues through blood vessels. Preliminary studies show that B. burgdorferi binds and passes through endothelial barriers in part mediated by host matrix metalloproteases. Since neutrophils infected by A. phagocytophilum are activated to release bioactive metalloproteases and chemokines, we examined the enhanced B. burgdorferi transmigration through vascular barriers with co-infection in vitro. To test whether endothelial transmigration is enhanced with co-infection, B. burgdorferi and A. phagocytophilum-infected neutrophils were co-incubated with EA.hy926 cells (HUVEC-derived) and human brain microvascular endothelial cells in Transwell cultures. Transmigration of B. burgdorferi through endothelial cell barriers was determined and endothelial barrier integrity was measured by transendothelial electrical resistivity. More B. burgdorferi crossed both human BMEC and EA.hy926 cells in the presence of A. phagocytophilum-infected neutrophils than with uninfected neutrophils without affecting endothelial cell integrity. Such a mechanism may contribute to increased blood and tissue spirochete loads.
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Nyarko
authors.forename: D J
authors.initials: DJ
authors.lastname: Grab
authors.forename: J S
authors.initials: JS
authors.lastname: Dumler
mesh_terms: D041081:Anaplasma phagocytophilum / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000382:microbiology; D025065:Borrelia burgdorferi / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D016873:Ehrlichiosis / Q000150:complications* / Q000382:microbiology; D042783:Endothelial Cells / Q000382:microbiology; D004730:Endothelium, Vascular / Q000382:microbiology; D006801:Humans; D008193:Lyme Disease / Q000150:complications* / Q000382:microbiology; D009504:Neutrophils / Q000382:microbiology* / Q000502:physiology