Does cytokine signaling link sphingolipid metabolism to host defense and immunity against virus infections?

Abstract

Sphingosine 1-phosphate (S1P)-metabolizing enzymes regulate the level of bioactive sphingolipids that have curative potential. Recently, S1P-metabolizing enzymes such as sphingosine kinase 1 and S1P lyase were shown to regulate influenza virus replication and the virus-induced cytopathogenicity. The mechanism appeared to employ a JAK/STAT type I interferon signaling pathway that induces anti-viral status. Further, sphingosine analogs altered cytokine responses upon influenza virus infection. This article focuses on recent discoveries about the sphingolipid system that influences on host protection from viral virulence and the involvement of cytokine signaling in its underlying mechanisms. Deciphering the steps of this pathway could help us envision how the modulation of sphingolipid metabolism can be applied as a therapeutic approach to overcome infectious diseases.

Figure 1. Regulation of influenza virus propagation by S1P-metabolizing enzymes

Sphingolipids with chemical structure and their metabolizing enzymes are shown. The impact of S1P-metabolizing enzymes on influenza virus replication and CPE is depicted.

Figure 2. Schematic models for S1P-metabolizing enzyme-mediated regulation of cytokine signaling to control virus replication

(A) In SK1-overexpressing cells, SK1-TRAF2 may form a multi-complex with IFNAR to trigger NF-κB signaling and block type I IFN signaling, which results in the enhancement of virus replication. TNF could also increase apoptosis leading to enhancement of virus replication or CPE. (B) The action mode of possible pro-viral NF-κB signaling is shown. (C) In SPL-overexpressing cells or DMS-treated cells, the SK1-TRAF2 complex may be destabilized leading to the blockade of pro-viral NF-κB signaling; in addition, this action could allow the activation of type I IFN signaling, which would interfere with virus replication. ERK may increase type I IFN signal activation and/or impair TNF-induced Bax/Bad activation.