Interferon Lambda Receptor-1 Isoforms Differentially Influence Gene Expression and HBV Replication in Stem Cell-derived Hepatocytes

Overview

Journal Antiviral Res

Publisher Elsevier

Date 2023 Dec 9

PMID 38070830

Authors

Laura A Novotny

J Grayson Evans

Haitao Guo

Christiana S Kappler

Eric G Meissner

Affiliations

Soon will be listed here.

Abstract

Background: In the tolerogenic liver, inadequate or ineffective interferon signaling fails to clear chronic HBV infection. Lambda IFNs (IFNL) bind the interferon lambda receptor-1 (IFNLR1) which dimerizes with IL10RB to induce transcription of antiviral interferon-stimulated genes (ISG). IFNLR1 is expressed on hepatocytes, but low expression may limit the strength and antiviral efficacy of IFNL signaling. Three IFNLR1 transcriptional variants are detected in hepatocytes whose role in regulation of IFNL signaling is unclear: a full-length and signaling-capable form (isoform 1), a form that lacks a portion of the intracellular JAK1 binding domain (isoform 2), and a secreted form (isoform 3), the latter two predicted to be signaling defective. We hypothesized that altering expression of IFNLR1 isoforms would differentially impact the hepatocellular response to IFNLs and HBV replication.

Methods: Induced pluripotent stem-cell derived hepatocytes (iHeps) engineered to contain FLAG-tagged, doxycycline-inducible IFNLR1 isoform constructs were HBV-infected then treated with IFNL3 followed by assessment of gene expression, HBV replication, and cellular viability.

Results: Minimal overexpression of IFNLR1 isoform 1 markedly augmented ISG expression, induced de novo proinflammatory gene expression, and enhanced inhibition of HBV replication after IFNL treatment without adversely affecting cell viability. In contrast, overexpression of IFNLR1 isoform 2 or 3 partially augmented IFNL-induced ISG expression but did not support proinflammatory gene expression and minimally impacted HBV replication.

Conclusions: IFNLR1 isoforms differentially influence IFNL-induced gene expression and HBV replication in hepatocytes. Regulated IFNLR1 expression in vivo could limit the capacity of this pathway to counteract HBV replication.

Citing Articles

Expression and function of interferon lambda receptor 1 variants.

Novotny L, Meissner E FEBS Lett. 2024; 599(4):466-475.

PMID: 39435588 PMC: 11850208. DOI: 10.1002/1873-3468.15041.

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