Abstract
Aspergillus fumigatus is the main cause of invasive fungal infections occurring almost exclusively in immunocompromised patients. An improved understanding of the initial innate immune response is key to the development of better diagnostic tools and new treatment options. Mice are commonly used to study immune defense mechanisms during the infection of the mammalian host with A. fumigatus. However, little is known about functional differences between the human and murine immune response against this fungal pathogen. Thus, we performed a comparative functional analysis of human and murine dendritic cells (DCs), macrophages, and polymorphonuclear cells (PMNs) using standardized and reproducible working conditions, laboratory protocols, and readout assays. A. fumigatus did not provoke identical responses in murine and human immune cells but rather initiated relatively specific responses. While human DCs showed a significantly stronger upregulation of their maturation markers and major histocompatibility complex molecules and phagocytosed A. fumigatus more efficiently compared to their murine counterparts, murine PMNs and macrophages exhibited a significantly stronger release of reactive oxygen species after exposure to A. fumigatus. For all studied cell types, human and murine samples differed in their cytokine response to conidia or germ tubes of A. fumigatus. Furthermore, Dectin-1 showed inverse expression patterns on human and murine DCs after fungal stimulation. These specific differences should be carefully considered and highlight potential limitations in the transferability of murine host–pathogen interaction studies.
Highlights
Humans inhale hundreds of airborne fungal spores daily, including spores from the saprophytic mold Aspergillus fumigatus, which is ubiquitous in the environment
Reactive oxygen species production by human and murine neutrophils and macrophages cocultured with A. fumigatus conidia or germ tubes was quantified and compared
Pro-inflammatory cytokine release was significantly induced by PMA stimulation, whereas coculture with A. fumigatus conidia did not result in significant induction of MIP1β or TNFα secretion
Summary
Humans inhale hundreds of airborne fungal spores daily, including spores from the saprophytic mold Aspergillus fumigatus, which is ubiquitous in the environment. Neutrophil granulocytes [polymorphonuclear cells (PMNs)] play a major role in the early immune defense against IA, as they are able to prevent germination and kill fungal hyphae through the release of ROS, phagocytosis, or formation of neutrophil extracellular traps. Dendritic cells (DCs) represent an important bridge between innate and adaptive immunity as they process fungal antigens and subsequently stimulate specific T-cells via antigen-presentation by major histocompatibility complex (MHC) I and II molecules. They orchestrate the immune response by secreting an array of pro- and anti-inflammatory cytokines. Stimulation of pattern recognition receptors (PRRs), such as toll-like receptors (TLR)-2 and -4 [3] and the Dectin1-receptor, is crucial to the activation of these immune cell subsets [4]
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