Grants and Contracts Details
Description
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.
Status | Finished |
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Effective start/end date | 8/15/03 → 10/31/07 |
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