Anaplasma - B. burgorferi/endothelijm interactions
Principal Investigator: DENNIS GRAB
Abstract: The manifestations of Lyme disease, caused by the deer tick-transmitted spirochete, Borrelia burgdorferi, range from skin infection to bloodstream invasion into the heart, joints, and nervous system. Human granulocytic anaplasmosis (HGA) is caused by Anaplasma phagocytophilum, a rickettsia of neutrophils that is also transmitted by the deer tick, Ixodes scapularis. Clinical investigations, serologic studies, and animal studies increasingly suggest that coinfection with A. phagocytophilum may contribute to severity and complications of Lyme disease. Most coinfection studies focus on A. phagocytophilum-modulated immune response to B. burgdorferi. However, a common link between tick-transmitted pathogens is access to blood for dissemination and the ability to pass through blood vessel walls. Preliminary studies show that B. burgdorferi binding and passage through endothelial cells is in part mediated by host matrix metalloproteases (MMPs), and that coincubations of B. burgdorferi and A. phagocytophilum-infected neutrophils with endothelial cells enhance transmigration of B. burgdorferi. A. phagocytophilum-infected neutrophils release chemokines and lose the ability to adhere to activated endothelial cells after significant loss of platelet selectin glycoprotein ligand (PSGL)-1 (CD162) and L-selectin (CD62L) adhesion molecule expression. While MMP inhibitors reverse L-selectin loss, only divalent cation chelators reverse shedding of surface PSGL-1. The data suggest the involvement of MMPs and a novel sheddase. Thus, a synergistic role for the novel PSGL-1 sheddase or chemokines is suggested in B. burgdorferi transmigration and dissemination. The hypothesis of the proposed research is that functional neutrophil changes triggered by A. phagocytophilum, including chemokine or MMP release, enhance the native ability of B. burgdorferi to transit across vascular barriers. We propose to: (1) quantify and define the kinetics of A. phagocytophilum enhanced B. burgdorferi transmigration across vascular and brain microvascular endothelial cells; and (2) define the specific B. burgdorferi transmigration enhancing factors such as MMPs, chemokines, or other biologically active products of A. phagocytophilum-infected cells. The results obtained from the proposed study will establish whether a distinctive non-immunologic role for coinfection exists in the dissemination of B. burgdorferi. The elucidation of the steps that explain the enhancement may allow for more intensive basic and clinical investigation into mechanisms of virulence for Lyme disease, HGE, and coinfections.
Funding Period: 2004-12-05 - 2007-11-30
more information: NIH RePORT
- Human granulocytic anaplasmosis and Anaplasma phagocytophilumJ Stephen Dumler
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Emerg Infect Dis 11:1828-34. 2005..More study is needed to define the immunology and pathogenetic mechanisms and to understand why severe disease develops in some persons and why some animals become long-term permissive reservoir hosts...
- Ehrlichioses in humans: epidemiology, clinical presentation, diagnosis, and treatmentJ Stephen Dumler
Division of Medical Microbiology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Clin Infect Dis 45:S45-51. 2007....
- Anaplasma phagocytophilum-Borrelia burgdorferi coinfection enhances chemokine, cytokine, and matrix metalloprotease expression by human brain microvascular endothelial cellsDennis J Grab
Department of Pediatrics, Johns Hopkins University School of Medicine, 200 North Wolfe Street, Room 3147, Baltimore, MD 21287, USA
Clin Vaccine Immunol 14:1420-4. 2007....
- Human brain microvascular endothelial cell traversal by Borrelia burgdorferi requires calcium signalingD J Grab
Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Clin Microbiol Infect 15:422-6. 2009..The data suggest a role for calcium signaling in CNS spirochete invasion through endothelial cell barriers...