Sphingosine 1-Phosphate-Metabolizing Enzymes Control Influenza Virus Propagation and Viral Cytopathogenicity

Abstract

Sphingosine 1-phosphate (S1P)-metabolizing enzymes regulate the level of sphingolipids and have important biological functions. However, the effects of S1P-metabolizing enzymes on host defense against invading viruses remain unknown. In this study, we investigated the role of S1P-metabolizing enzymes in modulating cellular responses to influenza virus infection. Overexpression of S1P lyase (SPL), which induces the degradation of S1P, interfered with the amplification of infectious influenza virus. Accordingly, SPL-overexpressing cells were much more resistant than control cells to the cytopathic effects caused by influenza virus infection. SPL-mediated inhibition of virus-induced cell death was supported by impairment of the upregulation of the proapoptotic protein Bax, a critical factor for influenza virus cytopathogenicity. Importantly, influenza virus infection of SPL-overexpressing cells induced rapid activation of extracellular signal-regulated kinase (ERK) and STAT1 but not of p38 mitogen-activated protein kinase (MAPK), Akt, or c-Jun N-terminal kinase (JNK). Blockade of STAT1 expression or inhibition of Janus kinase (JAK) activity elevated the level of influenza virus replication in the cells, indicating that SPL protects cells from influenza virus via the activation of JAK/STAT signaling. In contrast to that of SPL, the overexpression of S1P-producing sphingosine kinase 1 heightened the cells' susceptibility to influenza virus infection, an effect that was reversed by the inhibition of its kinase activity, representing opposed enzymatic activity. These findings indicate that the modulation of S1P-metabolizing enzymes is crucial for controlling the host defense against infection with influenza virus. Thus, S1P-metabolizing enzymes are novel potential targets for the treatment of diseases caused by influenza virus infection.

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

“…This demonstrates a specific requirement for SK1 and is consistent with prior reports of inhibition of viral replication by treatment of cells with chemical SK inhibitors (Machesky et al, 2008;Seo et al, 2010;Vijayan et al, 2014). Analysis of DENV infection in the setting of genetic ablation of SK1, represented by MEFs from SK1 2/2 embryos, yielded differing results, depending on whether the cells were from immortalized or primary cultures.…”

“…Accumulating evidence suggests a role for SK1 in promoting viral infection. In contrast however, to prior studies where overexpression of SK1 increased HCMV (Machesky et al, 2008), IAV (Seo et al, 2010) and measles virus infection (Vijayan et al, 2014), overexpression of SK1 did not influence DENV infectious virus release. This suggests that elevating SK1 in cells is of no additional benefit to DENV above any normal role of endogenous SK1.…”

“…Elevated SK1 has no effect on productive DENV infection Previous data have suggested that exogenous expression of SK1 in cells promotes HCMV, IAV and measles virus infection (Machesky et al, 2008;Seo et al, 2010;Vijayan et al, 2014). We quantified the level of endogenous SK1 in five different human cell lines and assessed their ability to support DENV infection.…”

“…Previous data suggested that targeting SK using broad-spectrum SK1/SK2 inhibitors reduced viral infection (Machesky et al, 2008;Seo et al, 2010;Vijayan et al, 2014 (Fig. 3a), with approximately a 1 log reduction in DENV infectious virus release at 24 h p.i.…”

“…For human cytomegalovirus (HCMV) (Machesky et al, 2008), respiratory syncytial virus (RSV) (Monick et al, 2004), influenza A virus (IAV) (Seo et al, 2010(Seo et al, , 2013 and measles virus (Vijayan et al, 2014), high levels of SK1 in cells prior to infection assist viral replication. The ability of SK1 to promote infection has been proposed to occur via a number of different mechanisms, such as preventing viral-induced cell death (Machesky et al, 2008;Monick et al, 2004), increasing production of viral RNA and export of viral proteins (Seo et al, 2013), NFk Bmediated effects on viral protein synthesis (Vijayan et al, 2014) and phosphorylation of STAT1 (Seo et al, 2011).…”