Eosinophil Deficiency Compromises Lung Defense against Aspergillus fumigatus

Abstract

ABSTRACTExposure to the moldAspergillus fumigatusmay result in allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, or invasive aspergillosis (IA), depending on the host's immune status. Neutrophil deficiency is the predominant risk factor for the development of IA, the most life-threatening condition associated withA. fumigatusexposure. Here we demonstrate that in addition to neutrophils, eosinophils are an important contributor to the clearance ofA. fumigatusfrom the lung. AcuteA. fumigatuschallenge in normal mice induced the recruitment of CD11b+Siglec F+Ly-6GloLy-6CnegCCR3+eosinophils to the lungs, which was accompanied by an increase in lungEpx(eosinophil peroxidase) mRNA levels. Mice deficient in the transcription factor dblGATA1, which exhibit a selective deficiency in eosinophils, demonstrated impairedA. fumigatusclearance and evidence of germinating organisms in the lung. Higher burden correlated with lower mRNA expression ofEpx(eosinophil peroxidase) andPrg2(major basic protein) as well as lower interleukin 1β (IL-1β), IL-6, IL-17A, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and CXCL1 levels. However, examination of lung inflammatory cell populations failed to demonstrate defects in monocyte/macrophage, dendritic cell, or neutrophil recruitment in dblGATA1-deficient mice, suggesting that the absence of eosinophils in dlbGATA1-deficient mice was the sole cause of impaired lung clearance. We show that eosinophils generated from bone marrow have potent killing activity againstA. fumigtausin vitro, which does not require cell contact and can be recapitulated by eosinophil whole-cell lysates. Collectively, our data support a role for eosinophils in the lung response afterA. fumigatusexposure.