PMID- 36314946
OWN - NLM
STAT- MEDLINE
DCOM- 20230105
LR  - 20230105
IS  - 2165-0497 (Electronic)
IS  - 2165-0497 (Linking)
VI  - 10
IP  - 6
DP  - 2022 Dec 21
TI  - 25-Hydroxycholesterol Mediates Cholesterol Metabolism to Restrict Porcine 
      Deltacoronavirus Infection via Suppression of Transforming Growth Factor beta1.
PG  - e0219822
LID - 10.1128/spectrum.02198-22 [doi]
LID - e02198-22
AB  - 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 beta1 
      (TGF-beta1), 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-beta1 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 TGFbeta1. 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-beta1 
      in CoV infection by bioinformatic analysis and verified that the inhibition of 
      TGF-beta1 showed anti-PDCoV capacity. Moreover, we uncovered the relationship 
      between TGF-beta and cholesterol metabolism initially. Given that the importance of 
      cholesterol in viral infection, 25HC has a great potential to treat PDCoV 
      infection and TGF-beta1 can be a crucial antiviral target.
FAU - Zhang, Jialu
AU  - Zhang J
AD  - Department of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, 
      Beijing, China.
FAU - Yang, Guanghui
AU  - Yang G
AD  - Department of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, 
      Beijing, China.
FAU - Wang, Xuefei
AU  - Wang X
AD  - Department of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, 
      Beijing, China.
FAU - Zhu, Yaohong
AU  - Zhu Y
AUID- ORCID: 0000-0003-0689-1679
AD  - Department of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, 
      Beijing, China.
FAU - Wang, Jiufeng
AU  - Wang J
AUID- ORCID: 0000-0002-0183-5611
AD  - Department of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, 
      Beijing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221031
PL  - United States
TA  - Microbiol Spectr
JT  - Microbiology spectrum
JID - 101634614
RN  - 767JTD2N31 (25-hydroxycholesterol)
RN  - 0 (Antiviral Agents)
RN  - 9008-11-1 (Interferons)
RN  - 0 (Transforming Growth Factor beta1)
RN  - Porcine coronavirus HKU15
SB  - IM
MH  - Animals
MH  - Antiviral Agents/pharmacology
MH  - *Coronavirus
MH  - *Coronavirus Infections/veterinary
MH  - Diarrhea
MH  - Interferons
MH  - Swine
MH  - *Swine Diseases/virology
MH  - Transforming Growth Factor beta1/metabolism
PMC - PMC9769798
OTO - NOTNLM
OT  - 25-hydroxycholesterol
OT  - TGF-beta1
OT  - cholesterol metabolism
OT  - lipid droplets
OT  - porcine deltacoronavirus
COIS- The authors declare no conflict of interest.
EDAT- 2022/11/01 06:00
MHDA- 2022/12/28 06:00
PMCR- 2022/10/31
CRDT- 2022/10/31 10:10
PHST- 2022/11/01 06:00 [pubmed]
PHST- 2022/12/28 06:00 [medline]
PHST- 2022/10/31 10:10 [entrez]
PHST- 2022/10/31 00:00 [pmc-release]
AID - 02198-22 [pii]
AID - spectrum.02198-22 [pii]
AID - 10.1128/spectrum.02198-22 [doi]
PST - ppublish
SO  - Microbiol Spectr. 2022 Dec 21;10(6):e0219822. doi: 10.1128/spectrum.02198-22. 
      Epub 2022 Oct 31.