Human and Murine Innate Immune Cell Populations Display Common and Distinct Response Patterns during Their In Vitro Interaction with the Pathogenic Mold Aspergillus fumigatus

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.

The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes

“…This suggests that Candidalysin seems to be more important for human cells as compared to murine cells, but could also be interpreted by the fact that several fungal factors exhibit redundancy in stimulating IL-1β and inducing cell death, particularly in murine phagocytes. Similarly, distinct inflammatory response patterns of murine and human macrophages have been observed when challenged with Aspergillus fumigatus 55 .…”

The domestic pig as human‐relevant large animal model to study adaptive antifungal immune responses against airborne Aspergillus fumigatus

“…Many of the differences in A. fumigatus infection dynamics and infection clearance reported for rodent models versus humans [27] can be explained by differences in size and morphometry of the lungs besides the increasing evidence of functional differences between the human and murine immune systems [28]. The use of domestic pigs as translational models for respiratory diseases is therefore becoming more important in bridging between small laboratory rodent models and human medicine [16], as they, compared to mice, more closely reflect human lung capacity, alveoli size, bronchial anatomy, and respiratory rates [14, 29‐31].…”

First Insights in NK—DC Cross-Talk and the Importance of Soluble Factors During Infection With Aspergillus fumigatus

“…Monocytes were isolated according to the manufacturer's instructions (CD14 positive selection, Miltenyi Biotec). To generate monocyte-derived dendritic cells, 10 ng/ml interleukin (IL)-4 (Miltenyi Biotec) and 100 ng/ml GM-CSF (Bayer) were applied to RPMI 1640 (Invitrogen) supplemented with 10 % fetal bovine serum (FBS, Sigma Aldrich) and 120 μg/ml gentamicin (Merck) for 5 days as reported recently (Mezger et al, 2008 ; Tan et al, 2013 ; Hellmann et al, 2017 ). DC generation was performed in 6-well plates (BD Falcon) with a cell concentration of 2.5 × 10 6 cells/3 ml.…”