The sphingosine kinase 1 activator, K6PC-5, attenuates Ebola virus infection

Imre, Gergely; Krähling, Verena; Eichler, Madeleine; Trautmann, Sandra; Ferreiròs, Nerea; Aman, M. Javad; Kashanchi, Fatah; Rajalingam, Krishnaraj; Pöhlmann, Stefan; Becker, Stephan; Heringdorf, Dagmar Meyer zu; Pfeilschifter, Josef

doi:10.1016/j.isci.2021.102266

Cited by 7 publications

(14 citation statements)

References 44 publications

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“…Interestingly, another study showed that a SK1 activator, K6PC-5, inhibited EBOV GP-mediated entry (21). Therefore, taken with our current study, this suggests that interfering with S1P production, whether it be positively or negatively, leads to inefficient EBOV entry.…”

Section: Discussionsupporting

confidence: 79%

“…Additionally, inhibitors of sphingosine kinase 1 (SK1) and sphingosine-1-phosphate G-protein coupled receptors (S1PR) were also identified, suggesting a role for the SK-S1PR axis in EBOV GP-mediated entry (18). Interestingly, Imre and colleagues reported that a sphingosine kinase 1 activator or the overexpression of SK1 reduced EBOV-GP mediated entry, further suggesting a role for SK1 in EBOV entry, although the mechanism remains to be elucidated (21).…”

Section: Introductionmentioning

confidence: 99%

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Sphingosine kinases promote Ebola virus infection and can be targeted to inhibit filoviruses, coronaviruses, and arenaviruses using late endocytic trafficking to enter cells

Stewart

et al. 2022

Preprint

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Entry of enveloped viruses in host cells requires the fusion of the viral and host cell membranes, a process that is facilitated by viral fusion proteins protruding from the viral envelope. For fusion, viral fusion proteins need to be triggered by host factors and for some viruses, such as Ebola virus (EBOV) and Lassa fever virus, this event occurs inside endosomes and/or lysosomes. Consequently, these late-penetrating viruses must be internalized and delivered to entry-conducive intracellular vesicles. Because endocytosis and vesicular trafficking are tightly regulated cellular processes, late penetrating viruses also depend on specific host factors, such as signaling molecules, for efficient viral delivery to the site of fusion, suggesting that these could be targeted for antiviral therapy. In this study, we investigated a role for sphingosine kinases (SKs) in viral entry and found that chemical inhibition of sphingosine kinase 1 (SK1) and/or SK2 and knockdown of SK1 or SK2, inhibited entry of EBOV into host cells. Mechanistically, inhibition of SK1 and/or SK2 prevented EBOV from reaching late-endosomes and lysosomes that are positive for the EBOV receptor, Niemann Pick C1 (NPC1). Furthermore, we present evidence that suggests the trafficking defect caused by SK1/2 inhibition occurs independently of S1P signaling through cell-surface S1PRs. Lastly, we found that chemical inhibition of SKs prevents entry of other late-penetrating viruses, including arenaviruses and coronaviruses, in addition to inhibiting infection by replication competent EBOV and SARS-CoV-2 in Huh7.5 cells. In sum, our results highlight an important role played by SKs in endocytic trafficking which can be targeted to inhibit entry of late-penetrating viruses. SK inhibitors could serve as a starting point for the development of broad-spectrum antiviral therapeutics.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Sphingosine kinases promote Ebola virus infection and can be targeted to inhibit filoviruses, coronaviruses, and arenaviruses using late endocytic trafficking to enter cells

Stewart

et al. 2022

Preprint

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“…Previous studies have shown that the inhibition of sphingosine kinase by bovine viral diarrhea virus NS3 is crucial for efficient viral replication and cytopathogenesis [ 33 ], and that the SphK1 activator K6PC-5 can alleviate Ebola virus infections [ 34 ]. However, Seo et al found that SphK1 plays a positive role in WSN (H1N1) virus infection and can promote the susceptibility of cells to the virus [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of the Interaction between Viral PB2 and Host SphK1 on H9N2 AIV Replication in Mammals

Zhou

Gao

Sun

et al. 2022

Viruses

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The H9N2 avian influenza virus (AIV) is currently widespread worldwide, posing a severe threat to the poultry industry and public health. Reassortment is an important way for influenza viruses to adapt to a new host. In 2007, the PB2 gene of H9N2 AIV in China was reassorted, and the DK1-like lineage replaced the F/98-like lineage, forming a dominant genotype of G57. This genotype and its reassortants (such as H7N9, H10N8 and H5N6) showed higher mammalian adaptation, and caused increased human infections. However, the adaptive mechanisms of the DK1-like lineage PB2 gene remain unclear. Here, we confirmed that the PB2 lineage of the H9N2 AIV currently prevalent in China still belongs to the DK1-like lineage and, compared with the previously predominant F/98-like lineage, the DK1-like lineage PB2 gene significantly enhances H9N2 AIV to mammalian adaptation. Through transcriptomic analysis and qRT–PCR and western blot experiments, we identified a host factor, sphingosine kinase 1 (SphK1), that is closely related to viral replication. SphK1 inhibits the replication of DK1-like PB2 gene H9N2 AIV, but the ability of SphK1 protein to bind DK1-like PB2 protein is weaker than that of F/98-like PB2 protein, which may contribute to H9N2 AIV containing the DK1-like PB2 gene to escape the inhibitory effect of host factor SphK1 for efficient infection. This study broadens our understanding of the adaptive evolution of H9N2 AIV and highlights the necessity to pay close attention to the AIV that contains the adaptive PB2 protein in animals and humans.

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“…A negative effect of elevated S1P concentrations induced by the SphK activator K6PC-5 has been observed for Ebolavirus infections. The effect was independent of S1P receptors and appears to be mediated intracellularly, affecting the viral entry process ( Imre et al, 2021 ). Thus, sphingosine kinases and intracellular S1P can have differential effects on virus replication depending on the virus and the target cell.…”

Section: Intracellular Sphingolipid Interactions During Viral Replicationmentioning

confidence: 99%

The Manifold Roles of Sphingolipids in Viral Infections

et al. 2021

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Sphingolipids are essential components of eukaryotic cells. In this review, we want to exemplarily illustrate what is known about the interactions of sphingolipids with various viruses at different steps of their replication cycles. This includes structural interactions during entry at the plasma membrane or endosomal membranes, early interactions leading to sphingolipid-mediated signal transduction, interactions with internal membranes and lipids during replication, and interactions during virus assembly and budding. Targeted interventions in sphingolipid metabolism – as far as they can be tolerated by cells and organisms – may open novel possibilities to support antiviral therapies. Human immunodeficiency virus type 1 (HIV-1) infections have intensively been studied, but for other viral infections, such as influenza A virus (IAV), measles virus (MV), hepatitis C virus (HCV), dengue virus, Ebola virus, and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), investigations are still in their beginnings. As many inhibitors of sphingolipid metabolism are already in clinical use against other diseases, repurposing studies for applications in some viral infections appear to be a promising approach.

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The sphingosine kinase 1 activator, K6PC-5, attenuates Ebola virus infection

Cited by 7 publications

References 44 publications

Sphingosine kinases promote Ebola virus infection and can be targeted to inhibit filoviruses, coronaviruses, and arenaviruses using late endocytic trafficking to enter cells

Sphingosine kinases promote Ebola virus infection and can be targeted to inhibit filoviruses, coronaviruses, and arenaviruses using late endocytic trafficking to enter cells

Effect of the Interaction between Viral PB2 and Host SphK1 on H9N2 AIV Replication in Mammals

The Manifold Roles of Sphingolipids in Viral Infections

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