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Cellular regulation of interferon lambda signaling by interferon lambda receptor 1 variants

Award Number: R01AI192546
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Cellular regulation of interferon lambda signaling by interferon lambda receptor 1 variants - PROJECT SUMMARY/ABSTRACT Lambda interferons (IFNLs) are cytokines that signal through a receptor heterodimer comprised of the lambda interferon receptor 1 (IFNLR1) and the interleukin-10 receptor subunit β to guide innate immune responses to pathogens encountered at mucosal surfaces, barrier sites, and the liver without inducing excessive inflammation. IFNLR1 has low and cell-type restricted expression in epithelial cells like hepatocytes, however the mechanisms cells use to regulate signaling through IFNLR1 are not understood. Several differentially sized IFNLR1 transcripts were identified in clinical samples and relative expression levels of each differs by cell type and correlates with IFNL-responsiveness. The predominant transcript in IFNL-responsive cells encodes for full-length, canonical IFNLR1, but cells also express two non-canonical transcripts that encode for truncated proteins predicted to be signaling defective. To evaluate IFNLR1 variant function, we used induced pluripotent stem cells with intact or abrogated endogenous IFNLR1 to generate hepatocyte-like cells (iHeps) with inducible expression of each FLAG-tagged IFNLR1 variant. We discovered that increased levels of canonical IFNLR1 supported higher expression of antiviral genes, allowed de novo expression of proinflammatory genes, and markedly enhanced the capacity of IFNLs to inhibit hepatitis B virus (HBV) replication. Increased expression of noncanonical IFNLR1 variants partially augmented IFNL-induced antiviral gene expression but failed to support expression of proinflammatory genes or enhance inhibition of HBV replication. Based on this work, we hypothesize that cells in vivo utilize low canonical IFNLR1 expression and expression of non-canonical IFNLR1 variants that differentially engage signaling pathways to control the nature of the cellular response to IFNLs. In Aim 1 of this proposal, we will use iHeps to define the mechanisms of differential signaling supported by IFNLR1 variants. We will determine their relative susceptibility to inhibition of signaling pathway components, examine their colocalization with signaling mediators, define their influence on the phosphoproteome, and investigate how they are internalized and trafficked. In Aim 2, we will use dCas9 and splice site modification to alter expression of IFNLR1 isoforms derived from the endogenous IFNLR1 promoter and evaluate the impact of IFNL treatment on gene expression and inhibition of HBV replication in iHeps. We will use liver organoids derived from normal human liver samples to independently evaluate how modulation of endogenous IFNLR1 transcript expression influences IFNL signaling. Our study will provide novel insight into how physiological regulation of IFNL signaling by IFNLR1 isoforms may restrict excessive inflammation, but at the expense of supporting an antiviral response that is inadequate to combat chronic infections. This work will advance our understanding of a critical pathway that guides the host response to pathogens encountered at mucosal surfaces and barrier sites and has potential to inform and encourage new approaches to target and modulate IFNL signaling to treat infections.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $679,090 )
2026	2026	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Allergy and Infectious Diseases Research	000	1	8/18/2026	NEW	$679,090
														Subtotal = $679,090

Grand Total All Awards = $679,090

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Cellular regulation of interferon lambda signaling by interferon lambda receptor 1 variants

Award Number: R01AI192546

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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