Interferon-λ3 Exacerbates the Inflammatory Response to Microbial Ligands: Implications for SARS-CoV-2 Pathogenesis

Scott A Read; Brian S Gloss; Christopher Liddle; Jacob George; Golo Ahlenstiel

doi:10.2147/JIR.S301476

Interferon-λ3 Exacerbates the Inflammatory Response to Microbial Ligands: Implications for SARS-CoV-2 Pathogenesis

J Inflamm Res. 2021 Apr 1:14:1257-1270. doi: 10.2147/JIR.S301476. eCollection 2021.

Authors

Scott A Read^{1

2

3}, Brian S Gloss⁴, Christopher Liddle³, Jacob George³, Golo Ahlenstiel^{1

2

3}

Affiliations

¹ Blacktown Clinical School, Western Sydney University, Blacktown, NSW, 2148, Australia.
² Blacktown Hospital, WSLHD, Blacktown, NSW, 2148, Australia.
³ Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia.
⁴ Westmead Research Hub, Westmead Institute for Medical Research, Westmead, NSW, 2145, Australia.

Abstract

Introduction: Interferon lambdas (IFN-λs) are antiviral cytokines that restrict pathogen infection and dissemination at barrier surfaces. Controlled expression of IFN-λs efficiently eliminates acute infections by activating a suite of interferon stimulated genes that inhibit viral propagation and activate local immune cells. Excessive or prolonged production of IFN-λs can however mediate tissue inflammation and disrupt epithelial barriers in both viral and non-viral disease. The mechanism by which IFN-λs drive this disease pathogenesis is poorly understood but may be caused by IFN-λ-mediated amplification of other innate immune signaling pathways.

Methods: Monocyte-derived macrophages were differentiated ± IFN-λ3 and treated with KDO-lipid A, poly I:C or zymosan, representing bacterial, viral or fungal ligands, respectively. Transcriptome and protein expression were quantified by RNA sequencing/PCR and ELISA/bead array, respectively. Bioinformatic analysis was used to define transcription factor profiles and signaling pathways amplified by IFN-λ3. Finally, the SARS-CoV-2 dataset GSE152075 was queried to compare the effects of IFNL versus IFNA expression in relation to viral load and nasopharyngeal transcriptomes.

Results: IFN-λ3 exacerbated inflammatory and chemotactic responses unique to each microbial ligand, as measured by RNA sequencing and by ELISA/bead array. Functional annotation identified pathways amplified by IFN-λ3, including inflammasome activation. Inflammasome amplification was confirmed in vitro, as measured by caspase 1 activity and IL-1β cleavage. Lastly, SARS-CoV-2 infected nasopharyngeal transcriptomes expressing IFN-λs but not IFN-αs were implicated in myeloid cell-driven pathogenesis including neutrophil degranulation, complement and coagulation cascades.

Discussion: These data suggest that IFN-λs contribute to disease pathology by exacerbating innate immune responses during chronic or severe disease states. IFN-λs may contribute to SARS-CoV-2 disease severity, however further study is required to confirm true causation.

Keywords: COVID-19; inflammation; innate immunity; interferon lambda.