Anaplasma - B. burgdorferi /endothelium interactions

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DESCRIPTION (provided by applicant): 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.