Dr. Meissner’s research defined how type-I and type-III interferon (IFN) signaling pathways interact to regulate antiviral immunity in hepatocytes.
The project tested the hypothesis that type-III IFNs (IFNλ) modulate type-I IFN responses through induction of negative regulatory pathways, thereby shaping the balance between effective antiviral defense and chronic inflammation. Using hepatitis C virus (HCV) as a model system, this work established a framework for understanding how interferon signaling contributes to viral persistence, clearance, and treatment response in liver disease.
Specific Aims
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Define how canonical and non-canonical IFNLR1 receptor isoforms regulate type-I interferon signaling
- Determine how the IFNL4 genetic polymorphism (rs368234815) drives variability in hepatocyte antiviral responses
Research Approach
The project employed induced pluripotent stem cell–derived hepatocytes (iHeps) combined with CRISPR-Cas9 genome editing to dissect interferon signaling pathways in a genetically controlled system. IFNLR1 receptor expression and isoform composition were manipulated to determine their impact on downstream signaling and interferon-stimulated gene expression. Genetic engineering of the IFNL4 locus enabled direct testing of clinically relevant variants that influence antiviral responses. Functional assays measured cytokine signaling, gene expression, and response to viral and innate immune stimuli.
Use of the Center's Core Resources
Cell Models Core
- Generation of iPSC-derived hepatocytes and CRISPR-engineered cell lines
Advanced Imaging Core
- Analysis of interferon signaling dynamics and protein interactions
Administrative and Biostatistics Core
- Study design, data analysis, and training support
Innovation
• Establishes a mechanistic link between type-III and type-I interferon signaling in hepatocytes
• Defines the functional role of IFNLR1 receptor isoforms in regulating immune responses
• Uses CRISPR-edited iPSC-derived hepatocytes to model genetic variation in antiviral immunity
Impact and Outcomes
This project provides critical insight into how interferon signaling is regulated during chronic viral infection and how genetic variation influences patient outcomes. By defining mechanisms through which type-III interferons suppress or modulate type-I responses, this work informs strategies to therapeutically manipulate immune pathways in diseases such as hepatitis B, hepatitis C, and HIV.
Participation in the
Center for Biomedical Research Excellence in Digestive & Liver Disease's program supported Dr. Meissner’s transition to independence and advanced his research program in viral immunology and translational hepatology.
