Porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus in pigs, is one of the major pathogens for lethal watery
diarrhea in piglets and poses a threat to public health because of its potential for interspecies transmission to humans.
25-Hydroxycholesterol (25HC), a derivative of
cholesterol, exhibits multiple potential modulating host responses to pathogens, including viruses and bacteria, as well as pathogen-induced
inflammation, while its
antiviral effect on PDCoV and how it mediates the biological process of host cells to counter against
infections remain poorly understood. Here, we thoroughly explored the
antiviral effect of 25HC on PDCoV
infection and tried to elucidate the underlying mechanisms. 25HC showed no toxic effect in LLC-PK1 cells and exerted
antiviral ability against PDCoV
infection in vitro. The viral cycle and time-of-addition analyses showed that 25HC mainly restricted the early and middle periods of the PDCoV postentry stage to inhibit
infection. 25HC regulated disordered
cholesterol metabolism induced by PDCoV
infection and stimulated
interferon-related lipid droplet accumulation.
Transforming growth factor β1 (TGF-β1), screened by bioinformatic analyses, seemed to play an important role in PDCoV
infection and was downregulated by 25HC. One interesting finding is that inhibition of TGF-β1 with the inhibitor
asiaticoside exhibited a similar
antiviral capacity to 25HC and demonstrated regulation of
cholesterol metabolism. Taking all of the findings together, we verified the
antiviral effect of 25HC on PDCoV through interference with
cholesterol metabolism, which may be related to its suppression of TGFβ1. IMPORTANCE As an emerging enteropathogenic coronavirus in pigs, porcine deltacoronavirus (PDCoV) causes giant economic loss in the pig industry because of lethal
diarrhea and possesses the potential for transmission from animals to humans. Several pieces of evidence have suggested the
antiviral potential of cholesterol-25-hydroxylase and importance of
cholesterol in
viral infection. This study reports that
25-hydroxycholesterol (25HC) significantly restricted PDCoV
infection through modulation of
cholesterol metabolism, and we identified that lipid droplets play important roles in
interferon response against
virus infection. Moreover, this study identified the importance of TGF-β1 in CoV
infection by bioinformatic analysis and verified that the inhibition of TGF-β1 showed anti-PDCoV capacity. Moreover, we uncovered the relationship between TGF-β and
cholesterol metabolism initially. Given that the importance of
cholesterol in
viral infection, 25HC has a great potential to treat PDCoV
infection and TGF-β1 can be a crucial
antiviral target.