Modeling Dengue Virus-Hepatic Cell Interactions Using Human Pluripotent Stem Cell-Derived Hepatocyte-like Cells

Area of Science:

• Virology
• Stem Cell Biology
• Hepatology

Background:

• Dengue virus (DENV) infection and pathology understanding is limited by inadequate cell and animal models.
• Effective dengue antivirals and vaccines require better models to study DENV-host interactions.

Purpose of the Study:

• To develop and utilize human pluripotent stem cell-derived hepatocytes (HLCs) as an in vitro model for DENV infection.
• To investigate the molecular mechanisms of DENV-hepatocyte interactions and cellular responses.

Main Methods:

• Differentiation of human pluripotent stem cells (hPSCs) into hepatocyte-like cells (HLCs).
• Infection of HLCs with DENV to study viral replication and host responses.
• Analysis of cellular changes, including interferon and NF-κB pathway activation, and gene expression.

Main Results:

• hPSC-derived HLCs supported persistent and productive DENV infection.
• DENV infection activated interferon pathways, protecting bystander cells and reducing apoptosis in infected cells.
• DENV infection activated the NF-κB pathway, leading to cytokine production and downregulation of liver-specific genes (e.g., albumin, coagulation factor V).

Conclusions:

• hPSC-derived hepatocytes serve as a valuable in vitro model for DENV infection research.
• This model elucidates key aspects of DENV-host interactions in hepatocytes, including immune signaling and functional gene regulation.