This proposal is directed at dissecting the immunopathogenetic mechanisms of A. phagocytophilum infection in its dichotomous ability to cause mild and severe disease. We previously identified supportive data and provide preliminary studies that show the importance of NK and NKT cells in the induction of inflammatory disease. Moreover, studies in mice and humans both provide evidence of macrophage activation and hemophagocytic syndrome-like processes as the potential basis of inflammatory tissue injury and severe disease. Since macrophage activation and hemophagocytic syndromes are biologically linked to defective cytotoxic cell responses that lack the ability to dampen and resolve inflammation, we propose here to study whether A. phagocytophilum infection induces defects in direct cell killing by cytotoxic cells such as NK, NKT, and CD8 T lymphocytes, yet does not alter the profile of induced proinflammatory and macrophage activating cytokines. We expect to study this by in vitro analyses using purified cells and bacteria as a highly defined and controlled experimental approach and to verify the results in vivo using the mouse model we developed. We anticipate that these studies could shed light on the specific immunological abnormalities that occur with A. phagocytophilum infection and allow a more focused and intensive search for targets that could provide new opportunities for therapeutic interventions that diminish the severe consequences of infection.
Human granulocytic anaplasmosis is an emerging tick-borne infection that can be mild or fatal. Research indicates that the bacterium can induce a disease that results from activation of the immune system that then is not properly turned off. This application proposes to examine in detail whether the defect can be identified in the laboratory and in a live infection model of the disease in mice. This could lead to new information on how disease occurs with this organism and others, and perhaps new information about ways to combat this infection or to change host cell function in other diseases.
|Walker, David H; Dumler, J Stephen (2015) The role of CD8 T lymphocytes in rickettsial infections. Semin Immunopathol 37:289-99|
|Kang, Yan-Jun; Diao, Xiu-Nian; Zhao, Gao-Yu et al. (2014) Extensive diversity of Rickettsiales bacteria in two species of ticks from China and the evolution of the Rickettsiales. BMC Evol Biol 14:167|
|Choi, Kyoung-Seong; Scorpio, Diana G; Dumler, J Stephen (2014) Stat1 negatively regulates immune-mediated injury with Anaplasma phagocytophilum infection. J Immunol 193:5088-98|
|Choi, Kyoung-Seong; Dumler, J Stephen (2013) Anaplasma phagocytophilum, interferon gamma production and Stat1 signaling. Microbiol Immunol 57:207-12|