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Effector Mechanisms of Innate Leukocytes in Neuropenic Invasive Aspergillosis

Park, Stacy J
Format
Thesis/Dissertation; Online
Author
Park, Stacy J
Advisor
Mehrad, Borna
Abstract
Healthy hosts have evolved multiple layers of innate immune responses that readily clear inhaled Aspergillus conidia without the development of disease or acquired immunity to this organism. Defects in neutrophil function and numbers are considered to be the most pervasive risk factor for the development of the severe fungal infection, invasive aspergillosis. However, most patients with this infection exhibit complicated immune defects and the problem can extend beyond neutrophil deficiency. The current work supports the hypothesis that NK and dendritic cells are critical components of innate anti-fungal defenses in neutropenic hosts following pulmonary exposure to Aspergillus. In the lungs of neutropenic mice with invasive aspergillosis, NK cells mediate their protective effect by acting as the major source of IFN-! during early infection. The absence of NK cells or IFN-! contributed equally to increased fungal susceptibility and worsen outcome in neutropenic mice challenged with Aspergillus. NK-derived IFN-! is an important anti-fungal defense mechanism as it led to enhanced antimicrobial effects of resident and recruited myeloid cells, and augmented the production of lung IFN-inducible chemokines that may mediate further recruitment of effector leukocytes. A marked accumulation of immature lung myeloid DCs occurs in the lungs of neutropenic mice following Aspergillus challenge. This was associated with an augmented influx of monocytes from the blood to the lung and at the same time, reduced efflux of DCs to the draining lymph nodes. The rapid recruitment of DCs to the lung was attributable to greatly elevated lung TNF expression, resulting in lung expression of CCL2 and CCL20 which, in turn, mediated recruitment of TNF-producing myeloid DC. This important positive-feedback loop in the lung of neutropenic mice provided a protective and beneficial during the early phase of invasive aspergillosis since depletion of the cells resulted in a marked increased in the lung fungal burden. In vitro studies demonstrate that DC maturation require neutrophil contact and DC-SIGN expression. These data show that neutrophils may play an important in modulating the host dendritic cell response to Aspergillus.
Language
English
Published
University of Virginia, Department of Microbiology, PHD (Doctor of Philosophy), 2010
Published Date
2010-05-01
Degree
PHD (Doctor of Philosophy)
Collection
Libra ETD Repository
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