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Histological Quantification to Determine Lung Fungal Burden in Experimental Aspergillosis
Published on: March 9, 2018
Invasive aspergillosis-on-chip: A quantitative treatment study of human Aspergillus fumigatus infection
T N M Hoang1, Z Cseresnyés2, S Hartung1
1Infections in Hematology and Oncology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany; Department of Hematology and Medical Oncology, Jena University Hospital, Jena, Germany.
Abstract:
Invasive pulmonary aspergillosis is associated with a high mortality rate and poses a direct threat to immunocompromised patients. Here, we present the invasive aspergillosis-on-chip (IAC) model to investigate Aspergillus fumigatus infection in vitro. The model allows the study of the lateral growth and the invasive behaviour of fungal hyphae from the epithelium into the endothelial cell layer in an alveolus-on-chip model. We established an algorithm-based analysis pipeline for three-dimensional confocal microscopy images to visualize and quantify fungal morphology, including hyphal growth and branching. Human macrophages in the IAC model partially inhibited the growth of the fungus, contributed to the release of proinflammatory cytokines (IL-1, IL-6, TNF) and chemokines (IL-8 and MCP-1) associated with an increased number of invasive hyphae. Similar to in vivo, the application of the fungistatic drug caspofungin limited the fungal growth and resulted in morphological changes of the hyphal tree previously described in other studies. The IAC infection model allows the identification and characterization of cellular infection targets and in vitro testing of antifungal drugs in clinically relevant concentrations. It thus represents a promising tool to broaden the understanding of pathogenicity and pathophysiology of invasive aspergillosis.
Insights
A new invasive aspergillosis-on-chip model effectively simulates Aspergillus fumigatus infection in vitro. This model aids in understanding fungal invasion and testing antifungal drugs for invasive pulmonary aspergillosis.
Area of Science:
- Medical Mycology
- Infectious Diseases
- Biotechnology
Background:
- Invasive pulmonary aspergillosis (IPA) presents a significant mortality risk, particularly for immunocompromised individuals.
- Current in vitro models have limitations in fully recapitulating the complex host-pathogen interactions of IPA.
Purpose of the Study:
- To develop and validate an innovative invasive aspergillosis-on-chip (IAC) model for studying Aspergillus fumigatus infection.
- To investigate fungal hyphal invasion dynamics and host immune responses within a human alveolus-on-chip system.
Main Methods:
- Development of an IAC model integrating epithelial and endothelial cell layers to mimic lung alveoli.
- Utilized 3D confocal microscopy and an algorithm-based analysis pipeline for quantitative assessment of fungal morphology and invasion.
- Incorporated human macrophages to evaluate their role in host defense and inflammatory responses.
Main Results:
- The IAC model successfully visualized and quantified the lateral growth and invasive behavior of Aspergillus fumigatus hyphae.
- Human macrophages demonstrated partial fungal growth inhibition and released key proinflammatory cytokines (IL-1, IL-6, TNF) and chemokines (IL-8, MCP-1).
- The fungistatic drug caspofungin, applied in clinically relevant concentrations, effectively limited fungal growth and induced characteristic morphological changes, mirroring in vivo observations.
Conclusions:
- The IAC model provides a robust platform for studying the pathogenicity and pathophysiology of invasive aspergillosis in vitro.
- This model facilitates the identification of cellular infection targets and enables the preclinical testing of antifungal therapies against Aspergillus fumigatus.
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