Human granulocytic anaplasmosis (HGA) is a tick-borne infection caused by Anaplasma phagocytophilum, an obligate intracellular bacterium of neutrophils. Infection is widespread: seroprevalence reaches 15% in some areas and severity ranges from subclinical to fatal. Severe complications include a toxic shock-like illness probably mediated by ? and diffuse macrophage activation. Pathogenicity in a mouse model is due to innate immunity and IFN? production. Virulence varies with growth in vitro, and the inflammatory component resides in the bacterial membrane. Thus, we hypothesize that induction of proinflammatory response depends on triggering innate immunity and macrophage activation. To test this we will use the mouse model to assess which cells produce proinflammatory cytokines and the role of cytotoxicity toward antigen presenting cells. The results will be tested in the equine model by examination of thrombocytopenia and its relationship to macrophage activation. Thus, we propose to: 1. Demonstrate that NK, NKT, or CDS cytotoxic cells are the major source of IFN? that drive innate immune and proinflammatory histopathology with A. phagocytophilum infection. 2. Identify the key component(s) of A. phagocytophilum membranes responsible for induction of innate immune-related inflammatory histopathology. 3. Demonstrate that the mechanism of thrombocytopenia in the equine model of HGA relates to destruction within cytokine-activated macrophages. The demonstration in vitro and in animal models that a specific membrane component of A. phagocytophilum drives proinflammatory responses would indicate a pathogenesis more similar to toxic shock syndrome and macrophage activation syndromes. Identification of the active component and its differential expression in virulent and reduced virulence bacteria would facilitate an understanding of disease triggers by A. phagocytophilum, despite its lack of LPS and peptidoglycan. Moreover, whether cytotoxic cell function is altered and promotes macrophage activation or hemophagocytic syndrome will be determined. This information will provide a framework for rational design of therapies aimed at modulating immune injury and could foster design of preventative measures aimed at immunization.
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