Transient inhibition of sphingosine kinases confers protection to influenza A virus infected mice

Xia, Chuan; Seo, Young-­Jin; Studstill, Caleb J.; Vijayan, Madhuvanthi; Wolf, Jennifer J.; Hahm, Bumsuk

doi:10.1016/j.antiviral.2018.08.010

Cited by 44 publications

(65 citation statements)

References 54 publications

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“…Moreover, de novo synthesis of ceramide was found to be upregulated in cells overexpressing S1P lyase (74). Therefore, our results complement the previous findings since S1P formation will reduce the cellular ceramide pool and thus increasing IAV replication (49,71,72). Ceramide analogues and mimetics have been proposed as potential immunotherapeutic remedies against viral infections (45).…”

Section: Discussionsupporting

confidence: 87%

“…Our data, as well as those previously published (49,71,72), suggest that ceramide and downstream products likely interferes with the IAV life cycle at various stages, including replication, protein transport, and assembly. Confirming the biological significance of our results in vivo is something that we are planning to investigate in future work.…”

Section: Discussionsupporting

confidence: 83%

“…Seo et al previously showed that overexpression of S1P lyase, the enzyme responsible for irreversible degradation of S1P, inhibited IAV propagation, whereas overproduction of S1P through upregulation of sphingosine kinase 1 enhanced IAV replication (49,71). Also, it was shown in mice that inhibiting SK protects the mice from lethal IAV infection (72). S1P has been shown to act as a noncompetitive inhibitor of CerS2, and thus its overexpression could dampen the cellular levels of ceramide (73).…”

Section: Discussionmentioning

confidence: 99%

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Ceramide Suppresses Influenza A Virus Replication In Vitro

Soudani

Hage‐Sleiman

Karam

et al. 2019

J Virol

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Annual influenza outbreaks are associated with significant morbidity and mortality worldwide despite the availability of seasonal vaccines. Influenza pathogenesis depends on the manipulation of host cell signaling to promote virus replication. Ceramide is a sphingosine-derived lipid that regulates diverse cellular processes. Studies highlighted the differential role of ceramide de novo biosynthesis on the propagation of various viruses. Whether ceramide plays, a role in influenza virus replication is not known. In this study, we assessed the potential interplay between the influenza A (IAV) and ceramide biosynthesis pathways. The accumulation of ceramide in human lung epithelial cells infected with influenza A/H1N1 virus strains was evaluated using thin-layer chromatography and/or confocal microscopy. Virus replication was assessed upon the regulation of the de novo ceramide biosynthesis pathway. A significant increase in ceramide accumulation was observed in cells infected with IAV in a dose-and time-dependent manner. Inoculating the cells with UV-inactivated IAV did not result in ceramide accumulation in the cells, suggesting that the induction of ceramide required an active virus replication. Inhibiting de novo ceramide significantly decreased ceramide accumulation and enhanced virus replication. The addition of exogenous C 6 -ceramide prior to infection mediated an increase in cellular ceramide levels and significantly attenuated IAV replication and reduced viral titers (Ϸ1 log10 PFU/ml unit). Therefore, our data demonstrate that ceramide accumulation through de novo biosynthesis pathway plays a protective and antiviral role against IAV infection. These findings propose new avenues for development of antiviral molecules and strategies. IMPORTANCE Understanding the effect of sphingolipid metabolism on viral pathogenesis provide important insights into the development of therapeutic strategies against microbial infections. In this study, we demonstrate a critical role of ceramide during influenza A virus infection. We demonstrate that ceramide produced through de novo biosynthesis possess an antiviral role. These observations unlock new opportunities for the development of novel antiviral therapies against influenza.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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Ceramide Suppresses Influenza A Virus Replication In Vitro

Soudani

Hage‐Sleiman

Karam

et al. 2019

J Virol

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“…SphK1 inhibition also altered the phosphorylation of ERK, p90RSK, and AKT, the upstream signals of RanBP3/CRM1 activation. In a later study, our lab found that inhibition of SphK1 protects mice against lethal challenge with IAV [60]. Therefore, harnessing SphK1 appears to be critical for effective IAV infection in vitro and in vivo.…”

Section: Sphk1 In Virus Replicationmentioning

confidence: 90%

Emerging Connections of S1P-Metabolizing Enzymes with Host Defense and Immunity During Virus Infections

Wolf

Studstill

Hahm

2019

Viruses

Self Cite

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The sphingosine 1-phosphate (S1P) metabolic pathway is a dynamic regulator of multiple cellular and disease processes. Identification of the immune regulatory role of the sphingosine analog FTY720 led to the development of the first oral therapy for the treatment of an autoimmune disease, multiple sclerosis. Furthermore, inhibitors of sphingosine kinase (SphK), which mediate S1P synthesis, are being evaluated as a therapeutic option for the treatment of cancer. In conjunction with these captivating discoveries, S1P and S1P-metabolizing enzymes have been revealed to display vital functions during virus infections. For example, S1P lyase, which is known for metabolizing S1P, inhibits influenza virus replication by promoting antiviral type I interferon innate immune responses. In addition, both isoforms of sphingosine kinase have been shown to regulate the replication or pathogenicity of many viruses. Pro- or antiviral activities of S1P-metabolizing enzymes appear to be dependent on diverse virus–host interactions and viral pathogenesis. This review places an emphasis on summarizing the functions of S1P-metabolizing enzymes during virus infections and discusses the opportunities for designing pioneering antiviral drugs by targeting these host enzymes.

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“…Sphingosin kinases (SphK) are lipid kinases that mediate conversion of sphingosine to bioactive lipid sphingosine 1phosphate (S1P) (67), a known modulator of central apoptotic pathways (68). IAV infections leads to increased expression and activation of SphK1 and SphK2 (29) and in vitro inhibition of SphK1 was shown to decrease IAV RNA synthesis via suppression of NFkB activation (69). Treatment of mice with specific inhibitors to either SphK1 or SphK2 or a pan-SphK inhibitor led to prolonged survival of mice following lethal IAV infection (29).…”

Section: Therapeutic Small Moleculesmentioning

confidence: 99%

Response Modifiers: Tweaking the Immune Response Against Influenza A Virus

et al. 2019

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Despite causing pandemics and yearly epidemics that result in significant morbidity and mortality, our arsenal of options to treat influenza A virus (IAV) infections remains limited and is challenged by the virus itself. While vaccination is the preferred intervention strategy against influenza, its efficacy is reduced in the elderly and infants who are most susceptible to severe and/or fatal infections. In addition, antigenic variation of IAV complicates the production of efficacious vaccines. Similarly, effectiveness of currently used antiviral drugs is jeopardized by the development of resistance to these drugs. Like many viruses, IAV is reliant on host factors and signaling-pathways for its replication, which could potentially offer alternative options to treat infections. While host-factors have long been recognized as attractive therapeutic candidates against other viruses, only recently they have been targeted for development as IAV antivirals. Future strategies to combat IAV infections will most likely include approaches that alter host-virus interactions on the one hand or dampen harmful host immune responses on the other, with the use of biological response modifiers (BRMs). In principle, BRMs are biologically active agents including antibodies, small peptides, and/or other (small) molecules that can influence the immune response. BRMs are already being used in the clinic to treat malignancies and autoimmune diseases. Repurposing such agents would allow for accelerated use against severe and potentially fatal IAV infections. In this review, we will address the potential therapeutic use of different BRM classes to modulate the immune response induced after IAV infections.

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Transient inhibition of sphingosine kinases confers protection to influenza A virus infected mice

Cited by 44 publications

References 54 publications

Ceramide Suppresses Influenza A Virus Replication In Vitro

Ceramide Suppresses Influenza A Virus Replication In Vitro

Emerging Connections of S1P-Metabolizing Enzymes with Host Defense and Immunity During Virus Infections

Response Modifiers: Tweaking the Immune Response Against Influenza A Virus

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