Interferon lambda 4 expression is suppressed by the host during viral infection

Hong, Mee Ae; Schwerk, Johannes; Lim, Chrissie; Kell, Alison; Jarret, Abigail; Pangallo, Joseph; Loo, Yueh–Ming; Liu, Shuanghu; Hagedorn, Curt H.; Gale, Michael; Savan, Ram

doi:10.1084/jem.20160437

Cited by 59 publications

(57 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Antiviral activity of IFN-λ4 was suggested to be comparable to the activities of other type-III IFNs (24, 26, 28). We now show that IFN-λ4 acts faster than other type-III IFNs in inducing acute antiviral response, but at the same time induces expression of negative regulators of IFN response as well.…”

Section: Discussionmentioning

confidence: 87%

“…Expression of endogenous IFNL4 mRNA in virally-infected samples has been reported by several studies (1, 8, 28, 29), however, expression of endogenous IFN-λ4 protein has been clearly demonstrated only by confocal microscopy in PHH treated with PolyI:C (1). To further explore this, we infected PHH from 11 liver donors with Sendai virus (SeV), as this virus has been shown to induce IFNL4 mRNA expression in hepatic cell lines (28).…”

Section: Resultsmentioning

confidence: 95%

“…To further explore this, we infected PHH from 11 liver donors with Sendai virus (SeV), as this virus has been shown to induce IFNL4 mRNA expression in hepatic cell lines (28). We detected strong induction of all type-III IFNs, including IFNL4 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…IFN-λ4 is unique among IFNs because it is poorly secreted and undetectable in media of virally-infected cells (1, 25, 26, 28). We show IFN-λ4 detection with Western blotting in lysates from SeV-infected PHH, and specifically from donors with the dG allele, consistent with our previous observations showing IFN-λ4 in PHH treated with Poly I:C (1).…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

Obajemu

Rao

Dilley

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

Type-III interferons (IFNs) are important mediators of antiviral immunity. IFN-λ4 is a unique type-III IFN because it is produced only in individuals who carry a dG allele of a genetic variant rs368234815-dG/TT. Counterintuitively, those individuals who can produce IFN-λ4, an antiviral cytokine, are also less likely to clear HCV infection. Here, we searched for unique functional properties of IFN-λ4 that might explain its negative effect on HCV clearance. We used fresh primary human hepatocytes (PHH) treated with recombinant type-III IFNs or infected with Sendai virus (SeV) to model acute viral infection, and subsequently validated our findings in HepG2 cell line models. Endogenous IFN-λ4 protein was detectable only in SeV-infected PHH from individuals with the dG allele, where it was poorly secreted but highly functional even at concentrations below 50 pg/ml. IFN-λ4 acted faster than other type-III IFNs in inducing antiviral genes as well as negative regulators of IFN response, such as USP18 and SOCS1. Transient treatment of PHH with IFN-λ4 but not IFN-λ3 caused a strong and sustained induction of SOCS1, and refractoriness to further stimulation with IFN-λ3. Our results suggest unique functional properties of IFN-λ4 that can be important in viral clearance and other clinical conditions.

show abstract

Section: Discussionmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

Obajemu

Rao

Dilley

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Unlike in mice, humans express IFNLR on hepatocytes, enabling a direct role for IFN-λ in HCV infection [18,19]. The protective IFNL3/4 SNP creates a premature stop codon in the IFNL4 gene and may promote HCV clearance through up-regulation of neighboring IFN-λ genes or up-regulation of ISG induction in response to IFN-α/β therapy [104,107–109]. HCV encodes inhibitors of IFN-α/β induction that are required for its replication, demonstrating the importance of ISG induction in cell-intrinsic HCV control [110].…”

Section: Potential Implications For Human Persistent Viral Infectionmentioning

confidence: 99%

The Role of Interferon in Persistent Viral Infection: Insights from Murine Norovirus

Nice

Robinson

Winkle

2018

Trends in Microbiology

View full text Add to dashboard Cite

Persistent viral infections result from evasion or avoidance of sterilizing immunity, extend the timeframe of virus transmission, and can trigger disease. Prior studies in mouse models of persistent infection have suggested that ineffective adaptive immune responses are necessary for persistent viral infection. However, recent work in the murine norovirus (MNV) model of persistent infection demonstrates that innate immunity can control both early and persistent viral replication independent of adaptive immune effector functions. Interferons (IFNs) are central to the innate control of persistent MNV, apart from a role in modulating adaptive immunity. Furthermore, subtypes of IFN play distinct tissue-specific roles in innate control of persistent MNV infection. Type I IFN (IFN-α/β) controls systemic replication and type III IFN (IFN-λ) controls MNV persistence in the intestinal epithelium. In this article, we will review recent findings in the MNV model, highlighting the role of IFNs and innate immunity in clearing persistent viral infection, and discussing the broader implications of these findings for control of persistent human infections.

show abstract

Viral infections in humans and mice with genetic deficiencies of the type I IFN response pathway

Meyts

Casanova

2021

Eur J Immunol

View full text Add to dashboard Cite

Type I IFNs are so‐named because they interfere with viral infection in vertebrate cells. The study of cellular responses to type I IFNs led to the discovery of the JAK‐STAT signaling pathway, which also governs the response to other cytokine families. We review here the outcome of viral infections in mice and humans with engineered and inborn deficiencies, respectively, of (i) IFNAR1 or IFNAR2, selectively disrupting responses to type I IFNs, (ii) STAT1, STAT2, and IRF9, also impairing cellular responses to type II (for STAT1) and/or III (for STAT1, STAT2, IRF9) IFNs, and (iii) JAK1 and TYK2, also impairing cellular responses to cytokines other than IFNs. A picture is emerging of greater redundancy of human type I IFNs for protective immunity to viruses in natural conditions than was initially anticipated. Mouse type I IFNs are essential for protection against a broad range of viruses in experimental conditions. These findings suggest that various type I IFN‐independent mechanisms of human cell‐intrinsic immunity to viruses have yet to be discovered.

show abstract

Interferon lambda 4 expression is suppressed by the host during viral infection

Abstract: Hong et al. show that IFNλ4 exhibits similar antiviral activity to IFNλ3. Humans deploy several mechanisms to limit expression of functional IFNλ4 through noncoding splice variants and nonfunctional protein isoforms.

Cited by 59 publications

References 40 publications

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

The Role of Interferon in Persistent Viral Infection: Insights from Murine Norovirus

Viral infections in humans and mice with genetic deficiencies of the type I IFN response pathway

Contact Info

Product

Resources

About