The cholesterol metabolite 25-hydroxycholesterol suppresses porcine deltacoronavirus via lipophagy inhibition and mTORC1 modulation

Jia-Lu Zhang ^1,2, Xue-Fei Wang ¹, Jia-Lin Li ¹

⁰National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.

Veterinary Research +

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January 31, 2025

View abstract on PubMed

Summary

25-Hydroxycholesterol (25HC) enhances antiviral defenses by promoting lipid droplet accumulation and inhibiting lipophagy, thereby controlling porcine deltacoronavirus (PDCoV) replication and improving piglet health.

Area Of Science

Virology
Cell Biology
Biochemistry

Background

25-Hydroxycholesterol (25HC) exhibits antiviral properties, but its role in regulating lipid metabolism and antiviral defense against porcine deltacoronavirus (PDCoV) remains unclear.
Cholesterol homeostasis and lipid droplet (LD) dynamics are critical for viral replication, yet the interplay with 25HC in PDCoV infection requires elucidation.

Purpose Of The Study

To investigate the antiviral mechanism of 25HC against PDCoV in vitro and in vivo.
To explore how 25HC influences lipid metabolism, specifically LD accumulation and lipophagy, in the context of PDCoV infection.
To determine the effect of 25HC on PDCoV-infected piglets' clinical outcomes and intestinal health.

Main Methods

Treatment of PDCoV-infected LLC-PK1 cells and piglets with 25HC.
Measurement of free cholesterol (FC) and triglyceride (TG) levels.
Assessment of LD accumulation, lipophagy, and lysosomal protein expression.
Analysis of transcription factor EB (TFEB) and mTORC1 signaling pathway activity.
Evaluation of clinical symptoms and intestinal injury in infected piglets.

Main Results

25HC treatment reduced FC levels and increased TG levels in PDCoV-infected cells and piglets.
25HC promoted LD accumulation by decreasing protein expression related to lipophagy and lysosomes.
25HC inhibited TFEB nuclear translocation and mTORC1 activity, consequently hindering lipophagy and PDCoV replication.
25HC administration alleviated clinical symptoms and intestinal damage in PDCoV-infected piglets.

Conclusions

25HC exerts antiviral effects against PDCoV by modulating lipid metabolism and promoting LD accumulation.
The antiviral mechanism involves the inhibition of lipophagy via TFEB and mTORC1 signaling pathways.
25HC demonstrates therapeutic potential for PDCoV infection by improving host defense and reducing viral pathogenesis.

Keywords:

25-Hydroxycholesterol Porcine coronavirus lipophagy piglets transcription factor EB

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