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Neutrophils are the hallmark of the acute inflammatory response and contribute to host defense by ingesting and killing most bacterial and fungal pathogens. This laboratory's long-standing interest is directed at increasing understanding of the antimicrobial systems of the neutrophil, especially those mediated by oxidative pathways.
Neutrophil are capable of generating a variety of reactive oxygen and nitrogen-based compounds (hydrogen peroxide, superoxide, singlet oxygen, hydroxyl radical, hypochlorous acid, and nitrating compounds), but it is not clear which of these are relevant to microbicidal events within the phagocyte. Recently we have used chemical modifications of whole bacteria within the phagocyte to learn about events within the phagocytic vacuole. For example, the myeloperoxidase antimicrobial system of the neutrophil is capable,
in vitro, of generating both nitrating and chlorinating compounds. We recently determined that in the neutrophil phagosome chlorination is the predominant reaction in the phagosome and that this reaction depends on the neutrophil enzyme myeloperoxidase..
We have also used bacterial metabolic responses to report on stressor events within the neutrophil phagosome. Extracting RNA from bacteria that were allowed to respond to conditions within the phagosome identified a number of genes that altered their expression under these conditions. One prominent group of upregulated genes is controlled by a common transcription factor, OxyR, which senses the oxidizing environment of the bacterium. Deletion of the
oxyR gene renders bacteria approximately 10-fold more susceptible to neutrophil killing. The laboratory is currently dissecting the elements of the OxyR response, using deletions of individual genes regulated by this transcription factor
(OxyR regulon), in order to gain a better understanding of E. coli responses to conditions within the neutrophil phagosome.
PUBLICATIONS
Rosen H, Crowley JR, Heinecke JW. Human neutrophils use the myeloperoxidase-hydrogen peroxide-chloride system to chlorinate but not nitrate bacterial proteins during phagocytosis. J Biol Chem 277:30463-8, 2002.
Staudinger BJ, Oberdoerster MA, Lewis PJ, Rosen H. mRNA expression profiles for Escherichia coli ingested by normal and phagocyte oxidase-deficient human neutrophils. J Clin Invest 110:1151-63, 2002.
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