Conserved Induction of Distinct Antiviral Signalling Kinetics by Primate Interferon Lambda 4 Proteins

Interferon lambdas (IFNλ) (also known as type III IFNs) are critical cytokines that combat infection predominantly at barrier tissues, such as the lung, liver, and gastrointestinal tract. Humans have four IFNλs (1–4), where IFNλ1–3 show ~80%–95% homology, and IFNλ4 is the most divergent displaying o...

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Autores principales:	Cuncai Guo, Dorothee Reuss, Jonathon D. Coey, Swathi Sukumar, Benjamin Lang, John McLauchlan, Steeve Boulant, Megan L. Stanifer, Connor G. G. Bamford
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	interferon lambda signalling antiviral IFNL4 kinetics Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/dfa5ef4c8962486d9e2125865902a27f
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spelling	oai:doaj.org-article:dfa5ef4c8962486d9e2125865902a27f2021-11-18T04:53:53ZConserved Induction of Distinct Antiviral Signalling Kinetics by Primate Interferon Lambda 4 Proteins1664-322410.3389/fimmu.2021.772588https://doaj.org/article/dfa5ef4c8962486d9e2125865902a27f2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.772588/fullhttps://doaj.org/toc/1664-3224Interferon lambdas (IFNλ) (also known as type III IFNs) are critical cytokines that combat infection predominantly at barrier tissues, such as the lung, liver, and gastrointestinal tract. Humans have four IFNλs (1–4), where IFNλ1–3 show ~80%–95% homology, and IFNλ4 is the most divergent displaying only ~30% sequence identity. Variants in IFNλ4 in humans are associated with the outcome of infection, such as with hepatitis C virus. However, how IFNλ4 variants impact cytokine signalling in other tissues and how well this is conserved is largely unknown. In this study, we address whether differences in antiviral signalling exist between IFNλ4 variants in human hepatocyte and intestinal cells, comparing them to IFNλ3. We demonstrate that compared to IFNλ3, wild-type human IFNλ4 induces a signalling response with distinct magnitudes and kinetics, which is modified by naturally occurring variants P70S and K154E in both cell types. IFNλ4’s distinct antiviral response was more rapid yet transient compared to IFNλ1 and 3. Additionally, divergent antiviral kinetics were also observed using non-human primate IFNλs and cell lines. Furthermore, an IFNλ4-like receptor-interacting interface failed to alter IFNλ1’s kinetics. Together, our data provide further evidence that major functional differences exist within the IFNλ gene family. These results highlight the possible tissue specialisation of IFNλs and encourage further investigation of the divergent, non-redundant activities of IFNλ4 and other IFNλs.Cuncai GuoDorothee ReussJonathon D. CoeySwathi SukumarBenjamin LangJohn McLauchlanSteeve BoulantSteeve BoulantSteeve BoulantMegan L. StaniferMegan L. StaniferConnor G. G. BamfordFrontiers Media S.A.articleinterferonlambdasignallingantiviralIFNL4kineticsImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	interferon lambda signalling antiviral IFNL4 kinetics Immunologic diseases. Allergy RC581-607
spellingShingle	interferon lambda signalling antiviral IFNL4 kinetics Immunologic diseases. Allergy RC581-607 Cuncai Guo Dorothee Reuss Jonathon D. Coey Swathi Sukumar Benjamin Lang John McLauchlan Steeve Boulant Steeve Boulant Steeve Boulant Megan L. Stanifer Megan L. Stanifer Connor G. G. Bamford Conserved Induction of Distinct Antiviral Signalling Kinetics by Primate Interferon Lambda 4 Proteins
description	Interferon lambdas (IFNλ) (also known as type III IFNs) are critical cytokines that combat infection predominantly at barrier tissues, such as the lung, liver, and gastrointestinal tract. Humans have four IFNλs (1–4), where IFNλ1–3 show ~80%–95% homology, and IFNλ4 is the most divergent displaying only ~30% sequence identity. Variants in IFNλ4 in humans are associated with the outcome of infection, such as with hepatitis C virus. However, how IFNλ4 variants impact cytokine signalling in other tissues and how well this is conserved is largely unknown. In this study, we address whether differences in antiviral signalling exist between IFNλ4 variants in human hepatocyte and intestinal cells, comparing them to IFNλ3. We demonstrate that compared to IFNλ3, wild-type human IFNλ4 induces a signalling response with distinct magnitudes and kinetics, which is modified by naturally occurring variants P70S and K154E in both cell types. IFNλ4’s distinct antiviral response was more rapid yet transient compared to IFNλ1 and 3. Additionally, divergent antiviral kinetics were also observed using non-human primate IFNλs and cell lines. Furthermore, an IFNλ4-like receptor-interacting interface failed to alter IFNλ1’s kinetics. Together, our data provide further evidence that major functional differences exist within the IFNλ gene family. These results highlight the possible tissue specialisation of IFNλs and encourage further investigation of the divergent, non-redundant activities of IFNλ4 and other IFNλs.
format	article
author	Cuncai Guo Dorothee Reuss Jonathon D. Coey Swathi Sukumar Benjamin Lang John McLauchlan Steeve Boulant Steeve Boulant Steeve Boulant Megan L. Stanifer Megan L. Stanifer Connor G. G. Bamford
author_facet	Cuncai Guo Dorothee Reuss Jonathon D. Coey Swathi Sukumar Benjamin Lang John McLauchlan Steeve Boulant Steeve Boulant Steeve Boulant Megan L. Stanifer Megan L. Stanifer Connor G. G. Bamford
author_sort	Cuncai Guo
title	Conserved Induction of Distinct Antiviral Signalling Kinetics by Primate Interferon Lambda 4 Proteins
title_short	Conserved Induction of Distinct Antiviral Signalling Kinetics by Primate Interferon Lambda 4 Proteins
title_full	Conserved Induction of Distinct Antiviral Signalling Kinetics by Primate Interferon Lambda 4 Proteins
title_fullStr	Conserved Induction of Distinct Antiviral Signalling Kinetics by Primate Interferon Lambda 4 Proteins
title_full_unstemmed	Conserved Induction of Distinct Antiviral Signalling Kinetics by Primate Interferon Lambda 4 Proteins
title_sort	conserved induction of distinct antiviral signalling kinetics by primate interferon lambda 4 proteins
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/dfa5ef4c8962486d9e2125865902a27f
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Conserved Induction of Distinct Antiviral Signalling Kinetics by Primate Interferon Lambda 4 Proteins

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