The sphingosine kinase 1 activator, K6PC-5, attenuates Ebola virus infection.
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ABSTRACT:
SUBMITTER: Imre G
PROVIDER: S-EPMC8005759 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chikungunya virus (CHIKV) is a re-emerging arbovirus in the alphavirus genus. Upon infection, it can cause severe joint pain that can last years in some patients, significantly affecting their quality of life. Currently, there are no vaccines or anti-viral therapies available against CHIKV. Its spread to the Americas from the eastern continents has substantially increased the count of the infected by millions. Thus, there is an urgent need to identify therapeutic targets for CHIKV treatment. A potential point of intervention is the sphingosine-1-phosphate (S1P) pathway. Conversion of sphingosine to S1P is catalyzed by Sphingosine kinases (SKs), which we previously showed to be crucial pro-viral host factor during CHIKV infection. In this study, we screened inhibitors of SKs and identified a novel potent inhibitor of CHIKV infection-SLL3071511. We showed that the pre-treatment of cells with SLL3071511 in vitro effectively inhibited CHIKV infection with an EC50 value of 2.91 µM under both prophylactic and therapeutic modes, significantly decreasing the viral gene expression and release of viral particles. Our studies suggest that targeting SKs is a viable approach for controlling CHIKV replication.
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Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease, wherein transforming growth factor ? (TGF-?) and sphingosine-1-phosphate (S1P) contribute to the pathogenesis of fibrosis. However, the in vivo contribution of sphingosine kinase (SphK) in fibrotic processes has not been documented. Microarray analysis of blood mononuclear cells from patients with IPF and SphK1- or SphK2-knockdown mice and SphK inhibitor were used to assess the role of SphKs in fibrogenesis. The expression of SphK1/2 negatively correlated with lung function and survival in patients with IPF. Also, the expression of SphK1 was increased in lung tissues from patients with IPF and bleomycin-challenged mice. Knockdown of SphK1, but not SphK2, increased survival and resistance to pulmonary fibrosis in bleomycin-challenged mice. Administration of SphK inhibitor reduced bleomycin-induced mortality and pulmonary fibrosis in mice. Knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and TGF-? secretion in a bleomycin-induced lung fibrosis mouse model that was accompanied by reduced phosphorylation of Smad2 and MAPKs in lung tissue. In vitro, bleomycin-induced expression of SphK1 in lung fibroblast was found to be TGF-? dependent. Taken together, these data indicate that SphK1 plays a critical role in the pathology of lung fibrosis and is a novel therapeutic target.
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Project description:Dengue virus (DENV) regulates sphingosine kinase (SK)-1 activity and chemical inhibition of SK1 reduces DENV infection. In primary murine embryonic fibroblasts (pMEFs) lacking SK1 however, DENV infection is enhanced and this is associated with induction of normal levels of interferon beta (IFN-β) but reduced levels of IFN-stimulated genes (ISGs). We have further investigated this link between SK1 and type I IFN responses. DENV infection downregulates cell-surface IFN-alpha receptor (IFNAR)1 in both wild-type (WT) and SK1-/- pMEF, but, consistent with poor ISG responses, shows reduced induction of phosphorylated (p)-STAT1 and key IFN regulatory factors (IRF)1 and -7 in SK1-/- pMEF. Direct IFN stimulation induced ISGs (viperin, IFIT1), CXCL10, IRF1 and -7 and p-STAT1. Responses, however, were significantly reduced in SK1-/- pMEF, except for IFN-stimulated CXCL10 and IRF7. Poor IFN responses in SK1-/- pMEF were associated with a small reduction in basal cell-surface IFNAR1 and IRF1 mRNA in uninfected SK1-/- compared with WT pMEF. In contrast, treatment of cells with the SK1 inhibitor, SK1-I or expression of an inhibitory SK1 short hairpin RNA (shRNA), both of which reduce DENV infection, does not alter basal IRF1 mRNA or affect type I IFN stimulation of p-STAT1. Thus, cells genetically lacking SK1 can induce many responses normally following DENV infection, but have adaptive changes in IFNAR1 and IRF1 that compromise DENV-induced type I IFN responses. This suggests a biological link between SK1 and IFN-stimulated pathways. Other approaches to reduce SK1 activity, however, do not influence these important antiviral pathways but reduce infection and may be useful antiviral strategies.
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Project description:Measles virus (MV) manipulates host factors to facilitate virus replication. Sphingosine kinase (SK) is an enzyme catalyzing the formation of sphingosine 1-phosphate and modulates multiple cellular processes including the host defense system. Here, we determined the role of SK1 in MV replication. Overexpression of SK1 enhanced MV replication. In contrast, inhibition of SK impaired viral protein expression and infectious virus production from cells expressing MV receptor, SLAM or Nectin-4. The inhibition of virus replication was observed when the cells were infected by vaccine strain or wild type MV or V/C gene-deficient MV. Importantly, SK inhibition suppressed MV-induced activation of NF-?B. The inhibitors specific to NF-?B signal pathway repressed the synthesis of MV proteins, revealing the importance of NF-?B activation for efficient MV replication. Therefore, SK inhibition restricts MV replication and modulates the NF-?B signal pathway, demonstrating that SK is a cellular factor critical for MV replication.
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Project description:Normalized Gene expression data used for meta-analysis from studies: GSE31747, GSE8317, GSE24943, GSE24125. We studied the changes in macaque and human peripheral blood cell gene expression after infection with Ebola Zaire virus (EBZ) to identify host responses that occur before the emergence of symptoms. We integrated data from in vivo and in vitro infection studies of macaque or human peripheral blood. We identified mRNAs that were differentially expressed at early, middle, and late times after infection. The EBZ early genes showing increased or decreased expression were then compared to literature-derived host responses to malaria, rhinovirus and influenza virus which identified the patterns unique to each pathogen. From the group of EBZ-specific genes, we next predicted those that encoded secreted or membrane-associated proteins. Pairs of these host response mRNAs or proteins could become candidates for differential diagnosis of an early EBZ infection, before the emergence of conventional symptoms. Four key immune response pathways that were activated early showed profoundly decreased expression at late times.
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Project description:This SuperSeries is composed of the SubSeries listed below.
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