Abstract
Aspergillus fumigatus airway infections are associated with increased rates of hospitalizations and declining lung function in patients with chronic lung disease. While the pathogenesis of invasive A. fumigatus infections is well studied, little is known about the development and progression of airway infections. Previous studies have demonstrated a critical role for the IL-1 cytokines, IL-1α and IL-1β in enhancing pulmonary neutrophil recruitment during invasive aspergillosis. Here we use a mouse model of A. fumigatus airway infection to study the role of these IL-1 cytokines in immunocompetent mice. In the absence of IL-1 receptor signaling, mice exhibited reduced numbers of viable pulmonary neutrophils and increased levels of neutrophil apoptosis during fungal airway infection. Impaired neutrophil viability in these mice was associated with reduced pulmonary and systemic levels of G-CSF, and treatment with G-CSF restored both neutrophil viability and resistance to A. fumigatus airway infection. Taken together, these data demonstrate that IL-1 dependent G-CSF production plays a key role for host resistance to A. fumigatus airway infection through suppressing neutrophil apoptosis at the site of infection.
Highlights
Healthy humans inhale hundreds of conidia of the ubiquitous mold Aspergillus fumigatus on a daily basis without developing pulmonary disease [1, 2]
Bronchoalveolar lavage sampling of infected airways is of limited value in this mouse model, as histopathologic examination of lungs reveals the presence of intrabronchial lesions that frequently obstruct the airways, reducing the ability to sample the distal airways
Ex vivo culture of lungs after 1 and 3 days of airway infection revealed the secretion of high levels of IL-1a and IL-1b in lungs of mice with A. fumigatus airway infection, as compared to lungs from uninfected mice or mice infected with sterile agar beads (Figure 1)
Summary
Healthy humans inhale hundreds of conidia of the ubiquitous mold Aspergillus fumigatus on a daily basis without developing pulmonary disease [1, 2]. Elimination of this fungal challenge relies on both the airway mucociliary elevator as well as phagocytosis and killing of conidia by alveolar macrophages and epithelial cells [3, 4]. Neutrophil Viability During Aspergillus Infection undergoing cytotoxic chemotherapy or stem cell transplantation, A. fumigatus conidia escape the impaired innate immune responses to germinate and invade tissues, producing a necrotizing, invasive pneumonitis known as invasive aspergillosis [5]. Numerous studies have probed the pathogenesis of invasive aspergillosis, little is known about the host and fungal factors governing the development and progression of chronic A. fumigatus airway infections
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