Aspergillus fumigatus infection and fibrosis

Aspergillus fumigatus is an environmental mold that is responsible for a life-threatening pneumonia
known as invasive aspergillosis. The infection begins with the inhalation of conidia (spores) into the lung. In a
healthy individual, the spores are cleared by the immune system. However, in the immunosuppressed
population, or patients in the ICU, failure to eradicate the fungus allows the spores to germinate. A. fumigatus
releases an armamentarium of degradative enzymes as it grows, resulting in severe damage to the lung
parenchyma. Fibroblasts are one of the major cell types that respond to tissue damage. In response to injury,
these cells differentiate into an activated state, which is required to stabilize the tissue and promote repair.
However, fibroblast activity is not restricted to matrix secretion; emerging evidence suggests that they also
possess the ability to detect microbial pathogens and to respond by secreting mediators with the potential to
contribute to pathogen clearance. In this grant, we propose to take advantage of unique genetic mouse models
that we have developed to determine the contribution of pulmonary fibroblasts to the outcome of A. fumigatus
exposure. We hypothesize that fibroblast activation in response to A. fumigatus-induced lung damage amplifies
a protective inflammatory response. The proposed aims will test this hypothesis by determining the dynamics of
fibroblast activation and deactivation in response to A. fumigatus in both immunocompetent and
immunosuppressed mice, the transcriptional response of fibroblasts to A. fumigatus exposure, and the
contribution of fibroblasts to pathogenic outcome in a mouse model of fibroblast ablation. The findings of this
study will provide new information on mechanisms of host defense against A. fumigatus and potentially other
pathogens that damage the human lung.
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Grant Number: 5R01AI159078-05
NIH Institute/Center: NIH
Principal Investigator: DAVID ASKEW