Inhibition of NADPH Oxidase by Anaplasma Phagocytophila

  • Carlyon, Jason (PI)

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Human granulocytic ehrlichiosis (HGE) is an emerging infection of the blood that results in leukopenia and thrombocytopenia. If left untreated, the disease can manifest itself as severe neutropenia, hypotension, shock, and may potentially be fatal due to myocarditis, pancarditis, or to opportunistic infections resulting from impaired host defense mechanisms. Recent evidence suggests that kidney and pancreas transplant recipients are at risk for contracting HGE. A. phagocytophila, the etiologic agent of HGE, persists within its mammalian host by colonizing neutrophils. This bacterium utilizes multiple strategies to prevent NAOPH oxidase superoxide anion (02-) production. It is established that the bacterium inhibits the mRNA expression of gp91PhOX, a component of NADPH oxidase. Preliminary data presented here demonstrates that A. phagocytophila also prevents transcription of rac2, the key factor of NADPH oxidase. I hypothesize that A. phagocytophila interferes with rac2 promoter activity, thereby inhibiting rac2transcription. Aims 1 and 2 seek to define the mechanisms responsible for the inhibition of rac2 transcription. Evidence suggests that, prior to preventing rac2 and gp91PhOX mRNA expression once inside the host cell, A. phagocytophila initially inhibits activation of preformed NADPH oxidase components during invasion. Activation of Rac2 represents the initial, integral step of NADPH oxidase assembly. Therefore, I hypothesize that A. phagocytophila inhibits Rac2 activation as a means for preventing NADPH oxidase activation. This will be investigated in Aim 3. Collectively, these studies will decipher the complex means by which A. phagocytophila prevents the neutrophil respiratory burst. In addition, these studies will lead to a more thorough understanding of neutrophil biology, specifically the factors that regulate rac2 mRNA expression and NADPH oxidase activation.
Effective start/end date8/15/0310/31/07


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