25-Hydroxycholesterol Mediates Cholesterol Metabolism to Restrict Porcine Deltacoronavirus Infection via Suppression of Transforming Growth Factor β1

Zhang, Jialü; Yang, Guanghui; Wang, Xuefei; Zhu, Yaohong; Wang, Jiufeng

doi:10.1128/spectrum.02198-22

Cited by 8 publications

(6 citation statements)

References 51 publications

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“…Among them, we found statin-based molecules and the 25-hydroxycholesterol. These results are quite surprising due to their antiviral effect detected in repositioning against human and veterinarian viruses [48][49][50]. Dynasore and genistein did not present any antiviral effect, which is in discordance with the study of Spiesschaert et al [31].…”

Section: Discussionmentioning

confidence: 54%

A Screening Study Identified Decitabine as an Inhibitor of Equid Herpesvirus 4 That Enhances the Innate Antiviral Response

Normand,

Thieulent,

Fortier

et al. 2024

Viruses

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Equid herpesvirus 4 (EHV-4) is a common respiratory pathogen in horses. It sporadically induces abortion or neonatal death. Although its contribution in neurological disorders is not clearly demonstrated, there is a strong suspicion of its involvement. Despite preventive treatments using vaccines against EHV-1/EHV-4, the resurgence of alpha-EHV infection still constitutes an important threat to the horse industry. Yet very few studies have been conducted on the search for antiviral molecules against EHV-4. A screening of 42 antiviral compounds was performed in vitro on equine fibroblast cells infected with the EHV-4 405/76 reference strain (VR2230). The formation of cytopathic effects was monitored by real-time cell analysis (RTCA), and the viral load was quantified by quantitative PCR. Aciclovir, the most widely used antiviral against alpha-herpesviruses in vivo, does not appear to be effective against EHV-4 in vitro. Potential antiviral activities were confirmed for eight molecules (idoxuridine, vidarabine, pritelivir, cidofovir, valganciclovir, ganciclovir, aphidicolin, and decitabine). Decitabine demonstrates the highest efficacy against EHV-4 in vitro. Transcriptomic analysis revealed the up-regulation of various genes implicated in interferon (IFN) response, suggesting that decitabine triggers the immune antiviral pathway.

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Section: Discussionmentioning

confidence: 54%

A Screening Study Identified Decitabine as an Inhibitor of Equid Herpesvirus 4 That Enhances the Innate Antiviral Response

Normand,

Thieulent,

Fortier

et al. 2024

Viruses

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“…The molecule 25-hydroxycholesterol (25HC) has been recognized for its potential to inhibit the entry and replication of various coronaviruses, including PEDV and SARS-CoV-2. This inhibitory activity is mainly achieved by interfering with viral fusion and entry into host cells and disrupting viral protein maturation [ 42 , 43 , 44 , 45 , 46 ]. To further investigate the effect of 25HC on pseudovirus rVSV-ΔG-EGFP-S infection, we pretreated Huh7 cells with 25HC at concentrations of 50 μM and 100 μM for 2 h and subsequently infected these cells with rVSV-ΔG-EGFP-S virus.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, 25-hydroxycholesterol is an oxidized derivative of cholesterol and has been identified as a potential antiviral compound against several enveloped viruses, such as HIV [ 54 ], Ebola [ 55 ], and Zika [ 56 ]. Recent studies have suggested that 25HC can inhibit the entry and replication of coronaviruses, including PEDV, SARS-CoV-2, and MERS-CoV [ 42 , 43 , 44 , 45 , 57 , 58 ]. The mechanism by which 25HC exerts its antiviral effects on coronaviruses is not yet fully understood.…”

Section: Discussionmentioning

confidence: 99%

Establishment of Replication Deficient Vesicular Stomatitis Virus for Studies of PEDV Spike-Mediated Cell Entry and Its Inhibition

Luo,

Lv,

et al. 2023

Microorganisms

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The porcine epidemic diarrhea virus (PEDV) is a highly contagious and virulent enteric coronavirus that causes severe enteric disease in pigs worldwide. PEDV infection causes profound diarrhea, vomiting, and dehydration in pigs of all ages, resulting in high mortality rates, particularly among neonatal piglets. The spike glycoprotein (S) of PEDV plays a crucial role in binding to the host cell receptor and facilitating fusion between the viral and host membranes. Pseudotyped viral particles featuring the PEDV S protein are valuable tools for investigating virus entry, identifying neutralizing antibodies, and developing small molecules to impede virus replication. In this study, we used a codon-optimized PEDV S protein to generate recombinant pseudotyped vesicular stomatitis virus (VSV) particles (rVSV-ΔG-EGFP-S). The full-length S protein was efficiently incorporated into VSV particles. The S protein pseudotyped VSV exhibited infectivity towards permissive cell lines of PEDV. Moreover, we identified a new permissive cell line, JHH7, which showed robust support for PEDV replication. In contrast to the SARS-CoV-2 spike protein, the removal of amino acids from the cytoplasmic tail resulted in reduced efficiency of viral pseudotyping. Furthermore, we demonstrated that 25-hydroxycholesterol inhibited rVSV-ΔG-EGFP-S entry, while human APN facilitated rVSV-ΔG-EGFP-S entry through the use of ANPEP knockout Huh7 cells. Finally, by transducing swine intestinal organoids with the rVSV-ΔG-EGFP-S virus, we observed efficient infection of the swine intestinal organoids by the PEDV spike-pseudotyped VSV. Our work offers valuable tools for studying the cellular entry of PEDV and developing interventions to curb its transmission.

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“…The antiviral effect of 25HC on SARS-CoV-2 is consistent with the induction of LDs ( 79 ). In our previous study, the early infection of PDCoV (porcine deltacoronavirus) at 8 h to some extent induces the accumulation of LDs, 25HC treatment induces abundant LDs and reduces the replication of PDCoV accompanied by upregulated IFN-β mRNA ( 87 ). The opposite effects of LDs demonstrate its antiviral potential by enhancing the interferon response to viral infection, meanwhile, indicate the inverse mechanisms utilized by viruses to hinder the early antiviral response of organisms.…”

Section: Hc and Cholesterol Metabolismmentioning

confidence: 99%

“…The expression of TGF-β signaling can be dramatically induced by PDCoV infection, which is reversed by 25HC. The application of TGF-β inhibitor reveals its regulatory effect on the genes related to cholesterol metabolism ( 87 ). The thorough mechanism of TGF-β in viral infection is yet to be fully demonstrated, but it might be a potential approach for viral invasion and target for 25HC action.…”

Section: Hc and Transforming Growth Factor-βmentioning

confidence: 99%

25-hydroxycholesterol: an integrator of antiviral ability and signaling

Zhang,

Zhu,

Wang

et al. 2023

Front. Immunol.

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Cholesterol, as an important component in mammalian cells, is efficient for viral entry, replication, and assembly. Oxysterols especially hydroxylated cholesterols are recognized as novel regulators of the innate immune response. The antiviral ability of 25HC (25-Hydroxycholesterol) is uncovered due to its role as a metabolic product of the interferon-stimulated gene CH25H (cholesterol-25-hydroxylase). With the advancement of research, the biological functions of 25HC and its structural functions have been interpreted gradually. Furthermore, the underlying mechanisms of antiviral effect of 25HC are not only limited to interferon regulation. Taken up by the special biosynthetic ways and structure, 25HC contributes to modulate not only the cholesterol metabolism but also autophagy and inflammation by regulating signaling pathways. The outcome of modulation by 25HC seems to be largely dependent on the cell types, viruses and context of cell microenvironments. In this paper, we review the recent proceedings on the regulatory effect of 25HC on interferon-independent signaling pathways related to its antiviral capacity and its putative underlying mechanisms.

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25-Hydroxycholesterol Mediates Cholesterol Metabolism to Restrict Porcine Deltacoronavirus Infection via Suppression of Transforming Growth Factor β1

Cited by 8 publications

References 51 publications

A Screening Study Identified Decitabine as an Inhibitor of Equid Herpesvirus 4 That Enhances the Innate Antiviral Response

A Screening Study Identified Decitabine as an Inhibitor of Equid Herpesvirus 4 That Enhances the Innate Antiviral Response

Establishment of Replication Deficient Vesicular Stomatitis Virus for Studies of PEDV Spike-Mediated Cell Entry and Its Inhibition

25-hydroxycholesterol: an integrator of antiviral ability and signaling

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