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25-Hydroxycholesterol restricts human norovirus replication in human intestinal enteroids
Verónica Costantini1, Wadzanai P Mboko2, Helen Wall2
1Viral Gastroenteritis Branch, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Journal of Virology
|October 21, 2025
Summary
25-hydroxycholesterol (25-HC) restricts human norovirus replication in intestinal cells. This cholesterol regulator boosts innate immunity and reduces viral load, offering potential for new norovirus therapies.
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Norovirus is a major cause of acute gastroenteritis globally.
- Human intestinal enteroid (HIE) systems facilitate norovirus research.
- 25-hydroxycholesterol (25-HC) is a key regulator of cholesterol and antiviral defense.
Purpose of the Study:
- To investigate the antiviral effects of 25-hydroxycholesterol (25-HC) on human norovirus replication.
- To determine if 25-HC can restrict norovirus in jejunal HIE monolayers.
- To explore the impact of 25-HC on host immune and metabolic pathways.
Main Methods:
- Jejunal HIE monolayers were treated with varying concentrations of 25-HC.
- Monolayers were infected with specific human norovirus genotypes (GII.1 and GII.4).
- Viral RNA was quantified using RT-qPCR at 1 and 24 hours post-infection.
Main Results:
- 25-HC demonstrated a dose-dependent restriction of norovirus replication across different HIE lines and genotypes.
- Upregulation of innate immunity genes (CCL2, CCL20, ICAM1, IL23A) was observed.
- Downregulation of cholesterol biosynthesis pathways, including ACAT2, was noted.
Conclusions:
- 25-HC exhibits significant antiviral activity against human norovirus in HIE models.
- Modulating 25-HC pathways enhances antiviral immune responses and restricts viral replication.
- Targeting 25-HC signaling presents a potential therapeutic strategy for norovirus infections.
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