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Interferon-λ3 Exacerbates the Inflammatory Response to Microbial Ligands: Implications for SARS-CoV-2 Pathogenesis
Scott A Read1,2,3, Brian S Gloss4, Christopher Liddle3
1Blacktown Clinical School, Western Sydney University, Blacktown, NSW, 2148, Australia.
Journal of Inflammation Research
|April 9, 2021
Summary
Interferon lambdas (IFN-λs) can worsen inflammatory responses and tissue damage in severe infections. These cytokines may increase severity in diseases like SARS-CoV-2 by amplifying innate immunity.
Area of Science:
- Immunology
- Virology
- Cytokine Biology
Background:
- Interferon lambdas (IFN-λs) are crucial antiviral cytokines that protect barrier surfaces by initiating interferon-stimulated genes.
- While essential for acute infections, excessive or prolonged IFN-λ production can lead to tissue inflammation and barrier disruption in various diseases.
- The precise mechanisms by which IFN-λs contribute to disease pathogenesis, potentially through amplifying other innate immune pathways, remain incompletely understood.
Purpose of the Study:
- To investigate how IFN-λ3 influences innate immune responses to bacterial, viral, and fungal ligands.
- To identify specific signaling pathways and transcription factors amplified by IFN-λ3.
- To compare the role of IFN-λ and IFN-α in SARS-CoV-2 infection pathogenesis.
Main Methods:
- Differentiated monocyte-derived macrophages were treated with microbial ligands (KDO-lipid A, poly I:C, zymosan) ± IFN-λ3.
- Quantified gene and protein expression via RNA sequencing, PCR, ELISA, and bead arrays.
- Analyzed transcriptomes from SARS-CoV-2 infected individuals (GSE152075) to compare IFNL and IFNA expression effects.
Main Results:
- IFN-λ3 amplified inflammatory and chemotactic responses to all tested microbial ligands.
- Bioinformatic analysis revealed amplification of pathways including inflammasome activation, confirmed by increased caspase 1 activity and IL-1β cleavage.
- In SARS-CoV-2 infections, elevated IFNL expression, unlike IFNA, correlated with myeloid cell-driven pathogenesis, including neutrophil degranulation and complement/coagulation cascades.
Conclusions:
- IFN-λs exacerbate innate immune responses, contributing to disease pathology in chronic or severe conditions.
- IFN-λs may play a role in SARS-CoV-2 disease severity by amplifying inflammatory pathways.
- Further research is necessary to establish a causal link between IFN-λs and SARS-CoV-2 pathogenesis.
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