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Assessing Anti-fungal Activity of Isolated Alveolar Macrophages by Confocal Microscopy
Published on: July 9, 2014
Dectin-1 and TLRs permit macrophages to distinguish between different Aspergillus fumigatus cellular states
Geoffrey M Gersuk1, David M Underhill, Liqun Zhu
1Fred Hutchinson Cancer Research Center, University of Washington, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Abstract:
Aspergillus fumigatus is a common cause of invasive and allergic pulmonary disease. Resting conidia of the filamentous fungus are constantly inhaled, but cause infection only after initiating hyphal growth. In this study, we have explored whether macrophages can distinguish between resting spores and the maturing, potentially invasive form of the fungus. Although macrophages bind and ingest A. fumigatus resting conidia efficiently, there is little inflammatory response; NF-kappabeta is not activated, inflammatory cytokines are not induced, and reactive oxygen species are not produced. However, maturing A. fumigatus conidia and germ tubes stimulate NF-kappabeta, secretion of proinflammatory cytokines and production of reactive oxygen by human monocyte-derived macrophages and murine macrophages from multiple anatomical sites. These responses are in part mediated by dectin-1, which binds cell wall beta-glucan that is not present on the surface of dormant conidia, but is present after cellular swelling and loss of the hydrophobic proteinaceous cell wall. Dectin-1 binding to germ tubes augments, but is not required for, TLR2-mediated inflammatory cytokine secretion. Dectin-1 recognition of germ tubes also stimulates TNF-alpha production in the absence of both TLR2 and MyD88 signaling. These data demonstrate one mechanism by which the pulmonary inflammatory response is tailored toward metabolically active cells, thereby avoiding unnecessary tissue damage with frequent inhalation of ubiquitous spores.
Insights
Macrophages can differentiate between resting and growing Aspergillus fumigatus spores. This prevents inflammation from inhaled spores, mounting an immune response only to the invasive, hyphal forms.
Area of Science:
- Immunology
- Mycology
- Pulmonary Medicine
Background:
- Aspergillus fumigatus spores are inhaled daily, but infection only occurs upon hyphal growth.
- Macrophages play a key role in the host defense against fungal pathogens.
- Understanding macrophage recognition of fungal forms is crucial for managing pulmonary diseases.
Purpose of the Study:
- To investigate if macrophages can distinguish between resting and growing Aspergillus fumigatus.
- To elucidate the mechanisms underlying macrophage inflammatory responses to different fungal forms.
Main Methods:
- Co-incubation of macrophages (human and murine) with resting and growing A. fumigatus conidia.
- Assessment of inflammatory markers: NF-kappaB activation, cytokine secretion, and reactive oxygen species (ROS) production.
- Investigation of the role of dectin-1 and TLR2 in macrophage recognition using knockout models.
Main Results:
- Macrophages efficiently bind and ingest resting conidia with minimal inflammatory response.
- Maturing conidia and germ tubes trigger significant inflammatory responses, including NF-kappaB activation, cytokine release, and ROS production.
- Dectin-1 binding to exposed beta-glucans on germ tubes is critical for initiating inflammatory responses, augmenting TLR2 signaling.
Conclusions:
- Macrophages differentiate between dormant and metabolically active A. fumigatus, preventing unnecessary inflammation from inhaled spores.
- Dectin-1-mediated recognition of fungal germ tubes is a key mechanism for initiating pulmonary inflammatory responses.
- This tailored response minimizes tissue damage from ubiquitous fungal spore inhalation.
