The LXR ligand GW3965 inhibits Newcastle disease virus infection by affecting cholesterol homeostasis

Sheng, Xiang-xiang; Sun, Yingjie; Zhan, Yuan; Qu, Yurong; Wang, Hua-xia; Luo, Miao; Liao, Ying; Qiu, Xusheng; Ding, Chan; Fan, Hongjie

doi:10.1007/s00705-016-2950-4

Cited by 15 publications

(9 citation statements)

References 47 publications

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“…Oxysterol production is inducible by IFNs ( Marquis et al, 2011 ; Blanc et al, 2013 ).These in turn activate LXR ( Lehmann et al, 1997 ), which boosts production of IFNγ ( Wang Q. et al, 2014 ). This could serve the purpose of inducing antiviral activity, as LXR has been described to induce viral restriction if induced pharmacologically ( Sheng et al, 2016 ; Lange et al, 2018 , 2019 ; Mlera et al, 2021 ). Further, oxysterols themselves exert similar antiviral effects against manifold viruses ( Civra et al, 2014 , 2018 ; Anggakusuma et al, 2015 ; Willard et al, 2018 ; Marcello et al, 2020 ; Zu et al, 2020 ; Glitscher et al, 2021 ).…”

Section: Innate Immunitymentioning

confidence: 99%

Endosomal Cholesterol in Viral Infections – A Common Denominator?

Glitscher

Hildt

2021

Front. Physiol.

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Cholesterol has gained tremendous attention as an essential lipid in the life cycle of virtually all viruses. These seem to have developed manifold strategies to modulate the cholesterol metabolism to the side of lipid uptake and de novo synthesis. In turn, affecting the cholesterol homeostasis has emerged as novel broad-spectrum antiviral strategy. On the other hand, the innate immune system is similarly regulated by the lipid and stimulated by its derivatives. This certainly requires attention in the design of antiviral strategies aiming to decrease cellular cholesterol, as evidence accumulates that withdrawal of cholesterol hampers innate immunity. Secondly, there are exceptions to the rule of the abovementioned virus-induced metabolic shift toward cholesterol anabolism. It therefore is of interest to dissect underlying regulatory mechanisms, which we aimed for in this minireview. We further collected evidence for intracellular cholesterol concentrations being less important in viral life cycles as compared to the spatial distribution of the lipid. Various routes of cholesterol trafficking were found to be hijacked in viral infections with respect to organelle-endosome contact sites mediating cholesterol shuttling. Thus, re-distribution of cellular cholesterol in the context of viral infections requires more attention in ongoing research. As a final aim, a pan-antiviral treatment could be found just within the transport and re-adjustment of local cholesterol concentrations. Thus, we aimed to emphasize the importance of the regulatory roles the endosomal system fulfils herein and hope to stimulate research in this field.

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Section: Innate Immunitymentioning

confidence: 99%

Endosomal Cholesterol in Viral Infections – A Common Denominator?

Glitscher

Hildt

2021

Front. Physiol.

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“…The effects of NDV infection on lipid metabolism in black-bone chickens have also been determined [16]. Moreover, disturbing cholesterol homeostasis can also inhibit NDV replication [17]. However, no systematic alterations in host cellular metabolites after vNDV infection have been reported.…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Metabolomic Profiling after Infection with Virulent Newcastle Disease Virus

Liu

Yin

Gong

et al. 2019

Viruses

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Newcastle disease (ND) is an acute, febrile, highly contagious disease caused by the virulent Newcastle disease virus (vNDV). The disease causes serious economic losses to the poultry industry. However, the metabolic changes caused by vNDV infection remain unclear. The objective of this study was to determine the metabolomic profiling after infection with vNDV. DF-1 cells infected with the vNDV strain Herts/33 and the lungs from Herts/33-infected specific pathogen-free (SPF) chickens were analyzed via ultra-high-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS) in combination with multivariate statistical analysis. A total of 305 metabolites were found to have changed significantly after Herts/33 infection, and most of them belong to the amino acid and nucleotide metabolic pathway. It is suggested that the increased pools of amino acids and nucleotides may benefit viral protein synthesis and genome amplification to promote NDV infection. Similar results were also confirmed in vivo. Identification of these metabolites will provide information to further understand the mechanism of vNDV replication and pathogenesis.

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“…Much of what is known about LXR biology in the context of viral infection has been defined using in vitro studies of RNA viruses and artificial synthetic LXR agonists. Activation of LXRs with artificial agonists was found to inhibit replication of hepatitis C virus (19,20), HIV (21)(22)(23), and Newcastle disease virus (24) in cell culture, likely through perturbations of cellular cholesterol content. Only a few in vivo studies have defined the effects of synthetic LXR agonists during virus infection.…”

mentioning

confidence: 99%

LXR Alpha Restricts Gammaherpesvirus Reactivation from Latently Infected Peritoneal Cells

Lange

Jondle

Darrah

et al. 2019

J Virol

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Gammaherpesviruses are ubiquitous viruses that establish lifelong infections. Importantly, these viruses are associated with numerous cancers and lymphoproliferative diseases. While risk factors for developing gammaherpesvirus-driven cancers are poorly understood, it is clear that elevated viral reactivation from latency often precedes oncogenesis. Here, we demonstrate that the liver X receptor alpha isoform (LXRα) restricts gammaherpesvirus reactivation in an anatomic-site-specific manner. We have previously demonstrated that deficiency of both LXR isoforms (α and β) leads to an increase in fatty acid and cholesterol synthesis in primary macrophage cultures, with a corresponding increase in gammaherpesvirus replication. Interestingly, expression of fatty acid synthesis genes was not derepressed in LXRα-deficient hosts, indicating that the antiviral effects of LXRα are independent of lipogenesis. Additionally, the critical host defenses against gammaherpesvirus reactivation, virus-specific CD8+ T cells and interferon (IFN) signaling, remained intact in the absence of LXRα. Remarkably, using a murine gammaherpesvirus 68 (MHV68) reporter virus, we discovered that LXRα expression dictates the cellular tropism of MHV68 in the peritoneal cavity. Specifically, LXRα−/− mice exhibit reduced latency within the peritoneal B cell compartment and elevated latency within F4/80+ cells. Thus, LXRα restricts gammaherpesvirus reactivation through a novel mechanism that is independent of the known CD8+ T cell-based antiviral responses or changes in lipid synthesis and likely involves changes in the tropism of MHV68 in the peritoneal cavity. IMPORTANCE Liver X receptors (LXRs) are nuclear receptors that mediate cholesterol and fatty acid homeostasis. Importantly, as ligand-activated transcription factors, LXRs represent potential targets for the treatment of hypercholesterolemia and atherosclerosis. Here, we demonstrate that LXRα, one of the two LXR isoforms, restricts reactivation of latent gammaherpesvirus from peritoneal cells. As gammaherpesviruses are ubiquitous oncogenic agents, LXRs may represent a targetable host factor for the treatment of poorly controlled gammaherpesvirus infection and associated lymphomagenesis.

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The LXR ligand GW3965 inhibits Newcastle disease virus infection by affecting cholesterol homeostasis

Cited by 15 publications

References 47 publications

Endosomal Cholesterol in Viral Infections – A Common Denominator?

Endosomal Cholesterol in Viral Infections – A Common Denominator?

In Vitro and In Vivo Metabolomic Profiling after Infection with Virulent Newcastle Disease Virus

LXR Alpha Restricts Gammaherpesvirus Reactivation from Latently Infected Peritoneal Cells

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