Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus

Walsh, Kevin B.; Teijaro, John R.; Wilker, Peter R.; Jatzek, Anna; Fremgen, Daniel; Das, Subash C.; Watanabe, Tokiko; Hatta, Masato; Shinya, Kyoko; Suresh, M.; Kawaoka, Yoshihiro; Rosen, Hugh; Oldstone, Michael B. A.

doi:10.1073/pnas.1107024108

Cited by 218 publications

(228 citation statements)

References 41 publications

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“…Several lines of evidence support the idea that increased production of chemokines and cytokines in response to influenza may contribute to pathology during influenza infection. For example, overabundant chemokines have been linked to increased pathogenicity and morbidity in influenza infection in humans (38), and blockade of influenza-induced cytokines protects against influenza mortality in mice without increasing viral titers in infected tissue (39). Significantly, in murine models, influenza preferentially induces monocyte-attracting chemokines, such as MIP-1β (40).…”

Section: Discussionmentioning

confidence: 99%

Enhanced natural killer-cell and T-cell responses to influenza A virus during pregnancy

Kay¹,

Fukuyama²,

Aziz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Pregnant women experience increased morbidity and mortality after influenza infection, for reasons that are not understood. Although some data suggest that natural killer (NK)-and T-cell responses are suppressed during pregnancy, influenza-specific responses have not been previously evaluated. Thus, we analyzed the responses of women that were pregnant (n = 21) versus those that were not (n = 29) immediately before inactivated influenza vaccination (IIV), 7 d after vaccination, and 6 wk postpartum. Expression of CD107a (a marker of cytolysis) and production of IFN-γ and macrophage inflammatory protein (MIP) 1β were assessed by flow cytometry. Pregnant women had a significantly increased percentage of NK cells producing a MIP-1β response to pH1N1 virus compared with nonpregnant women pre-IIV [median, 6.66 vs. 0.90% (P = 0.0149)] and 7 d post-IIV [median, 11.23 vs. 2.81% (P = 0.004)], indicating a heightened chemokine response in pregnant women that was further enhanced by the vaccination. Pregnant women also exhibited significantly increased T-cell production of MIP-1β and polyfunctionality in NK and T cells to pH1N1 virus pre-and post-IIV. NK-and T-cell polyfunctionality was also enhanced in pregnant women in response to the H3N2 viral strain. In contrast, pregnant women had significantly reduced NK-and T-cell responses to phorbol 12-myristate 13-acetate and ionomycin. This type of stimulation led to the conclusion that NK-and T-cell responses during pregnancy are suppressed, but clearly this conclusion is not correct relative to the more biologically relevant assays described here. Robust cellular immune responses to influenza during pregnancy could drive pulmonary inflammation, explaining increased morbidity and mortality.

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Section: Discussionmentioning

confidence: 99%

Enhanced natural killer-cell and T-cell responses to influenza A virus during pregnancy

Kay¹,

Fukuyama²,

Aziz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…S1PR1 expression in pDCs and its functional coupling to turnover of IFNAR1 and STAT1 down-modulation may reflect an evolutionary pathway suited to therapeutic exploitation. We have shown that S1PR1 agonism protects from influenza and mouse pulmonary virus immunopathology while allowing full development of sterilizing immunity, neutralizing Abs, and quantitatively normal immunological memory (10,(20)(21)(22)(23). Thus, blunting, but not abolishing, IFN-I amplification by the S1P/S1PR1 signaling axis allows host defense from pathogens.…”

Section: Significancementioning

confidence: 99%

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification

Teijaro

Studer

Leaf

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Blunting immunopathology without abolishing host defense is the foundation for safe and effective modulation of infectious and autoimmune diseases. Sphingosine 1-phosphate receptor 1 (S1PR1) agonists are effective in treating infectious and multiple autoimmune pathologies; however, mechanisms underlying their clinical efficacy are yet to be fully elucidated. Here, we uncover an unexpected mechanism of convergence between S1PR1 and interferon alpha receptor 1 (IFNAR1) signaling pathways. Activation of S1PR1 signaling by pharmacological tools or endogenous ligand sphingosine-1 phosphate (S1P) inhibits type 1 IFN responses that exacerbate numerous pathogenic conditions. Mechanistically, S1PR1 selectively suppresses the type I IFN autoamplification loop in plasmacytoid dendritic cells (pDCs), a specialized DC subset, for robust type I IFN release. S1PR1 agonist suppression is pertussis toxin-resistant, but inhibited by an S1PR1 C-terminal-derived transactivating transcriptional activator (Tat)-fusion peptide that blocks receptor internalization. S1PR1 agonist treatment accelerates turnover of IFNAR1, suppresses signal transducer and activator of transcription 1 (STAT1) phosphorylation, and downmodulates total STAT1 levels, thereby inactivating the autoamplification loop. Inhibition of S1P-S1PR1 signaling in vivo using the selective antagonist Ex26 significantly elevates IFN-α production in response to CpG-A. Thus, multiple lines of evidence demonstrate that S1PR1 signaling sets the sensitivity of pDC amplification of IFN responses, thereby blunting pathogenic immune responses. These data illustrate a lipid G-protein coupled receptor (GPCR)-IFNAR1 regulatory loop that balances effective and detrimental immune responses and elevated endogenous S1PR1 signaling. This mechanism will likely be advantageous in individuals subject to a range of inflammatory conditions. sphingosine 1-phosphate | S1PR1 | plasmacytoid dendritic cell | interferon-α | IFNAR1

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“…The product of SK activity, S1P, can have intracellular signalling functions or be secreted from cells to act on cell surface S1P receptors (Leclercq & Pitson, 2006;Rosen et al, 2014;Spiegel & Milstien, 2011;Xia & Wadham, 2011). A number of studies have shown that modulating the S1P/receptor can reduce virus-induced disease and tissue injury associated with IAV (Marsolais et al, 2009;Walsh et al, 2011) and in an animal model of RSV infection (Walsh et al, 2014). Thus, studies of the SK-virus interaction are of significant interest to potential therapeutic interventions for viral diseases.…”

Section: Introductionmentioning

confidence: 99%

Reduction in sphingosine kinase 1 influences the susceptibility to dengue virus infection by altering antiviral responses

Clarke

Davies

Calvert

et al. 2016

Journal of General Virology

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Sphingosine kinase (SK) 1 is a host kinase that enhances some viral infections. Here we investigated the ability of SK1 to modulate dengue virus (DENV) infection in vitro. Overexpression of SK1 did not alter DENV infection; however, targeting SK1 through chemical inhibition resulted in reduced DENV RNA and infectious virus release. DENV infection of SK1 2/2 murine embryonic fibroblasts (MEFs) resulted in inhibition of infection in an immortalized line (iMEF) but enhanced infection in primary MEFs (18MEFs). Global cellular gene expression profiles showed expected innate immune mRNA changes in DENV-infected WT but no induction of these responses in SK1 2/2 iMEFs. Reverse transciption PCR demonstrated a low-level induction of IFN-b and poor induction of mRNA for the interferon-stimulated genes (ISGs) viperin, IFIT1 and CXCL10 in DENV-infected SK1 2/2 compared with WT iMEFs. Similarly, reduced induction of ISGs was observed in SK1 2/2 18MEFs, even in the face of high-level DENV replication. In both iMEFs and 18MEFs, DENV infection induced production of IFN-b protein. Additionally, higher basal levels of antiviral factors (IRF7, CXCL10 and OAS1) were observed in uninfected SK1 2/2 iMEFs but not 18MEFs. This suggests that, in this single iMEF line, lack of SK1 upregulates the basal levels of factors that may protect cells against DENV infection. More importantly, regardless of the levels of DENV replication, all cells that lacked SK1 produced IFN-b but were refractory to induction of ISGs such as viperin, IFIT1 and CXCL10. Based on these findings, we propose new roles for SK1 in affecting innate responses that regulate susceptibility to DENV infection.

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Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus

Cited by 218 publications

References 41 publications

Enhanced natural killer-cell and T-cell responses to influenza A virus during pregnancy

Enhanced natural killer-cell and T-cell responses to influenza A virus during pregnancy

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification

Reduction in sphingosine kinase 1 influences the susceptibility to dengue virus infection by altering antiviral responses

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