Abstract
Inhalation of fungal spores (conidia) occurs commonly and, in specific circumstances, can result in invasive disease. We investigated the murine inflammatory response to conidia of Aspergillus fumigatus, the most common invasive mold in immunocompromised hosts. In contrast to dormant spores, germinating conidia induce neutrophil recruitment to the airways and TNF-α/MIP-2 secretion by alveolar macrophages. Fungal β-glucans act as a trigger for the induction of these inflammatory responses through their time-dependent exposure on the surface of germinating conidia. Dectin-1, an innate immune receptor that recognizes fungal β-glucans, is recruited in vivo to alveolar macrophage phagosomes that have internalized conidia with exposed β-glucans. Antibody-mediated blockade of Dectin-1 partially inhibits TNF-α/MIP-2 induction by metabolically active conidia. TLR-2- and MyD88-mediated signals provide an additive contribution to macrophage activation by germinating conidia. Selective responsiveness to germinating conidia provides the innate immune system with a mechanism to restrict inflammatory responses to metabolically active, potentially invasive fungal spores.
Highlights
The innate immune system confronts a wide spectrum of microbes, extending from the innocuous to the highly pathogenic [1,2,3]
bronchoalveolar lavage (BAL) fluid recovered from mice that were infected with live conidia contained 3.0 6 1.2 3 106 cells (Figure 1A) with a predominant neutrophilic infiltrate consisting of Ly6Ghi, CD11bþ, and CD11cÀ cells (Figure 1B; unpublished data)
BAL fluid collected from mice administered PBS-Tween contained only 0.97 6 0.17 3 105 cells with .90% alveolar macrophage (AMØ)
Summary
The innate immune system confronts a wide spectrum of microbes, extending from the innocuous to the highly pathogenic [1,2,3]. Robust inflammatory responses can compromise host tissues and organ function, which, in the case of the lungs, can be severely debilitating or even lethal. Lung airways are perpetually exposed to inhaled particulate materials that include pollens, viruses, and bacterial and fungal spores. While many of these particles are innocuous, some spores have the potential to germinate and cause invasive diseases. Distinguishing these rare pathogenic microbes from the innocuous majority and calibrating inflammatory responses to the invasive potential of the microbe are fundamental challenges faced by the pulmonary innate immune system
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