Aspergillus fumigatus Triggers Inflammatory Responses by Stage-Specific β-Glucan Display

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. Aspergillus fumigatus is a mold that forms spores that are often inhaled by mammals. Humans with normal immune systems inhale several hundred A. fumigatus spores per day without developing detectable disease. Immunocompromised hosts, on the other hand, can develop invasive A. fumigatus infections. In these cases, inhaled spores germinate and form tissue-invasive hyphae that invade blood vessels and disseminate to remote tissues. The aim of this study was to investigate the normal inflammatory response to inhaled spores in mouse lungs. The researchers found that the earliest stage of spore germination, referred to as “swelling,” triggered the recruitment of inflammatory cells into the lung airways. Consistent with this finding, lung-derived cells stimulated with swollen spores secreted copious amounts of proteins that attract inflammatory cells. Analysis of spores revealed that swelling is accompanied by surface expression of β-glucan polymers. These carbohydrates, which are not present on the surface of mammalian cells, induce signaling by the mammalian Dectin-1 receptor and activate the expression of genes that promote the inflammatory response. The results suggest that mammalian lungs have evolved a mechanism to distinguish swollen and potentially threatening spores from innocuous, dormant spores.