Granulocytic Ehrlichiosis: Cell-Pathogen Interactions

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DESCRIPTION (provided by applicant): Human granulocytic ehrlichiosis (HGE) is an emerging, potentially fatal, tick-borne zoonotic disease caused by an obligate intracellular bacterium. Although Anaplasma phagocytophila, formerly the HGE agent, lives and replicates primarily within granulocytes, multiple cytopenias, especially thrombocytopenia, are a consistent hallmark of infection. The interaction of A. phagocytophila with neutrophils and platelets in vivo and the manner in which these interactions contribute to infection efficiency, cytopenias, pathogen distribution and transmission are still unclear. The goal of this project is to understand pathogen interaction with host cells in light of hematologic abnormalities and in vivo infection kinetics utilizing a murine model of HGE and in vitro cell techniques. Study objectives are first, to determine leukocyte and platelet interaction with, and response to, A. phagocytophila and, second, to determine the role, if any, these interactions play in determining pathogen distribution and transmission. The central hypothesis for the proposed research, based on preliminary data, is that during early infection, A. phagocytophila adheres to and activates both granulocytes and platelets resulting in alterations in cell adhesion and distribution that directly affect cell-pathogen trafficking and facilitate pathogen replication and transmission. The proposed work is focused on an emerging, zoonotic disease with potentially serious hematologic alterations. Significant positive impacts of this work will include enhanced understanding of in vivo bacterial pathogenesis as well as elucidation of possible targets for interruption of the transmission cycle from animal host to tick vector. The purpose of the proposed Mentored Clinical Scientist Development (KO8) award is to provide the candidate with the mentoring and resources needed for transition into the position of an independent academic clinician-scientist. The award is ideally suited to this candidate who has completed her professional veterinary degree, clinical pathology training and PhD in Comparative Pathology but has not completed postdoctoral research training. Currently, the candidate is a junior faculty member at a strong research institution with a clear mandate and desire to pursue an independent research program.