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

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

Scott A Read,1– 3 Brian S Gloss,4 Christopher Liddle,3 Jacob George,3 Golo Ahlenstiel1– 3 1Blacktown Clinical School, Western Sydney University, Blacktown, NSW, 2148, Australia; 2Blacktown Hospital, WSLHD, Blacktown, NSW, 2148, Australia; 3Storr Liver Centre, The Westmead Institu...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Read SA, Gloss BS, Liddle C, George J, Ahlenstiel G
Formato: article
Lenguaje:EN
Publicado: Dove Medical Press 2021
Materias:
interferon lambda
inflammation
covid-19
innate immunity
Pathology
RB1-214
Therapeutics. Pharmacology
RM1-950
Acceso en línea:https://doaj.org/article/ff76d58668bc4406af89821d23fe6fe4
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:ff76d58668bc4406af89821d23fe6fe4
record_format dspace
spelling oai:doaj.org-article:ff76d58668bc4406af89821d23fe6fe42021-12-02T13:56:03ZInterferon-λ3 Exacerbates the Inflammatory Response to Microbial Ligands: Implications for SARS-CoV-2 Pathogenesis1178-7031https://doaj.org/article/ff76d58668bc4406af89821d23fe6fe42021-04-01T00:00:00Zhttps://www.dovepress.com/interferon-lambda3-exacerbates-the-inflammatory-response-to-microbial--peer-reviewed-article-JIRhttps://doaj.org/toc/1178-7031Scott A Read,1– 3 Brian S Gloss,4 Christopher Liddle,3 Jacob George,3 Golo Ahlenstiel1– 3 1Blacktown Clinical School, Western Sydney University, Blacktown, NSW, 2148, Australia; 2Blacktown Hospital, WSLHD, Blacktown, NSW, 2148, Australia; 3Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia; 4Westmead Research Hub, Westmead Institute for Medical Research, Westmead, NSW, 2145, AustraliaCorrespondence: Scott A Read Email s.read@westernsydney.edu.auIntroduction: 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-λ 3 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-λ 3. 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-λ 3 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-λ 3, 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: interferon lambda, inflammation, COVID-19, innate immunityRead SAGloss BSLiddle CGeorge JAhlenstiel GDove Medical Pressarticleinterferon lambdainflammationcovid-19innate immunityPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 1257-1270 (2021)
institution DOAJ
collection DOAJ
language EN
topic interferon lambda
inflammation
covid-19
innate immunity
Pathology
RB1-214
Therapeutics. Pharmacology
RM1-950
spellingShingle interferon lambda
inflammation
covid-19
innate immunity
Pathology
RB1-214
Therapeutics. Pharmacology
RM1-950
Read SA
Gloss BS
Liddle C
George J
Ahlenstiel G
Interferon-λ3 Exacerbates the Inflammatory Response to Microbial Ligands: Implications for SARS-CoV-2 Pathogenesis
description Scott A Read,1– 3 Brian S Gloss,4 Christopher Liddle,3 Jacob George,3 Golo Ahlenstiel1– 3 1Blacktown Clinical School, Western Sydney University, Blacktown, NSW, 2148, Australia; 2Blacktown Hospital, WSLHD, Blacktown, NSW, 2148, Australia; 3Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia; 4Westmead Research Hub, Westmead Institute for Medical Research, Westmead, NSW, 2145, AustraliaCorrespondence: Scott A Read Email s.read@westernsydney.edu.auIntroduction: 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-λ 3 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-λ 3. 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-λ 3 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-λ 3, 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: interferon lambda, inflammation, COVID-19, innate immunity
format article
author Read SA
Gloss BS
Liddle C
George J
Ahlenstiel G
author_facet Read SA
Gloss BS
Liddle C
George J
Ahlenstiel G
author_sort Read SA
title Interferon-λ3 Exacerbates the Inflammatory Response to Microbial Ligands: Implications for SARS-CoV-2 Pathogenesis
title_short Interferon-λ3 Exacerbates the Inflammatory Response to Microbial Ligands: Implications for SARS-CoV-2 Pathogenesis
title_full Interferon-λ3 Exacerbates the Inflammatory Response to Microbial Ligands: Implications for SARS-CoV-2 Pathogenesis
title_fullStr Interferon-λ3 Exacerbates the Inflammatory Response to Microbial Ligands: Implications for SARS-CoV-2 Pathogenesis
title_full_unstemmed Interferon-λ3 Exacerbates the Inflammatory Response to Microbial Ligands: Implications for SARS-CoV-2 Pathogenesis
title_sort interferon-λ3 exacerbates the inflammatory response to microbial ligands: implications for sars-cov-2 pathogenesis
publisher Dove Medical Press
publishDate 2021
url https://doaj.org/article/ff76d58668bc4406af89821d23fe6fe4
work_keys_str_mv AT readsa interferonlambda3exacerbatestheinflammatoryresponsetomicrobialligandsimplicationsforsarscov2pathogenesis
AT glossbs interferonlambda3exacerbatestheinflammatoryresponsetomicrobialligandsimplicationsforsarscov2pathogenesis
AT liddlec interferonlambda3exacerbatestheinflammatoryresponsetomicrobialligandsimplicationsforsarscov2pathogenesis
AT georgej interferonlambda3exacerbatestheinflammatoryresponsetomicrobialligandsimplicationsforsarscov2pathogenesis
AT ahlenstielg interferonlambda3exacerbatestheinflammatoryresponsetomicrobialligandsimplicationsforsarscov2pathogenesis
_version_ 1718392416712523776

Ejemplares similares