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Dectin-1 Promotes Type I and III Interferon Expression to Support Optimal Antifungal Immunity in the Lung
Orchi Dutta1,2, Vanessa Espinosa2, Keyi Wang1,2
1Graduate School of Biomedical Sciences, Rutgers Biomedical and Health Sciences, Newark, NJ, United States.
Abstract:
Pulmonary infections with Aspergillus fumigatus (Af) are a significant cause of invasive fungal disease and lead to high morbidity and mortality in diverse populations throughout the world. Currently available antifungal drugs are often ineffective, thus contributing to unacceptably high mortality rates in patients suffering from invasive fungal infections. The use of cytokines as adjunctive immune therapies holds the promise of significantly improving patient outcomes in the future. In recent studies, we identified an essential role for type I and III interferons as regulators of optimal antifungal responses by pulmonary neutrophils during infection with Af. Although various membrane and cytosolic nucleic acid sensors are known to regulate interferon production in response to viruses, the pathways that regulate the production of these cytokines during fungal infection remain uncovered. In the current study, we demonstrate that dectin-1-mediated recognition of β-glucan on the cell wall of the clinically relevant fungal pathogen Aspergillus fumigatus promotes the activation of a protective cascade of type I and III interferon expression. We further demonstrate that exogenous administration of type I and III interferons can rescue inadequate antifungal responses in dectin-1-/- mice, suggesting the potential therapeutic benefit of these cytokines as activators of antifungal defense in the context of innate defects.
Insights
Dectin-1 recognition of Aspergillus fumigatus triggers protective interferons. Supplementing type I and III interferons can enhance antifungal defenses, offering therapeutic potential for invasive fungal infections.
Area of Science:
- Immunology
- Mycology
- Infectious Diseases
Background:
- Pulmonary infections caused by Aspergillus fumigatus (Af) lead to high mortality due to ineffective antifungal drugs.
- Cytokines show promise as adjunctive therapies for invasive fungal infections.
- The pathways regulating interferon production during fungal infections are not fully understood.
Purpose of the Study:
- To investigate the role of dectin-1 in recognizing Aspergillus fumigatus and initiating antifungal immune responses.
- To explore the potential of type I and III interferons as therapeutic agents against Af infections.
Main Methods:
- Utilized dectin-1-deficient mice models to study Aspergillus fumigatus infection.
- Analyzed the expression of type I and III interferons following fungal recognition.
- Administered exogenous type I and III interferons to assess their therapeutic efficacy.
Main Results:
- Dectin-1-mediated recognition of beta-glucan on Aspergillus fumigatus activates a protective cascade of type I and III interferon expression.
- Exogenous administration of type I and III interferons rescued inadequate antifungal responses in dectin-1 knockout mice.
- This highlights the crucial role of dectin-1 and interferons in controlling pulmonary fungal infections.
Conclusions:
- Dectin-1 is a key sensor for Aspergillus fumigatus, initiating crucial interferon-mediated antifungal immunity.
- Type I and III interferons represent a promising therapeutic strategy for invasive pulmonary aspergillosis, particularly in immunocompromised individuals.
- Targeting dectin-1-interferon pathways could improve outcomes for patients with invasive fungal diseases.
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