Characterization of Pulmonary Fibroblast Response to Aspergillosis Fumigatus Exposure and Clinical Implications on the Development of Invasive Aspergillosis.

Aspergillosis fumigatus(AF) is a ubiquitous environmental mold that spreads by producing airborne conidia (spores). Playing a crucial role in the recycling of environmental carbon and nitrogen, A. fumigatus is inhaled abundantly by animals and humans alike. Unfortunately, it is also responsible for one of the worst life-threatening pneumonias known as invasive aspergillosis with a mortality rate above 30%, even with treatment. Healthy individuals that are immunocompetent can quickly clear inhaled AF spores before their germination via immune cells. However, in immunocompromised individuals the inability to clear the fungus allows the spores to germinate releasing a plethora of proteolytic enzymes as they infiltrate the tissue resulting in severe damage to the lung. Recent studies have shown that the proper response of the immune system hinges upon complex cellular cross-talk between resident interstitial cells and circulating immune cells. Tissue resident fibroblasts, which are responsible for the production and maintenance of the extracellular matrix (ECM), have been recently suggested to play a pivotal role in regulating immune response. We hypothesize that A. fumigatus-induced damage to the lungs would result in activation of pulmonary fibroblasts (PFs) and aid in protective inflammatory response. Utilizing our recently developed in vivo cre-loxP lineage tracing mouse models we have interrogated and manipulated all activated lung fibroblasts during AF infection, clearing, and reinfection. Data from our lab shows that PFs can be activated following acute inhalation of AF spores even when they are cleared from the lungs of immunocompetent mice before pathological tissue damage occurs. Furthermore, repeated AF infections which are pathologically asymptomatic result in the accumulation of activated PFs. Here we show for the first time that fibroblast activation occurs in both transient and chronic pulmonary infections revealing a role in the immunomodulatory response and subsequent development of pulmonary disease.