Virus interactions with the sphingolipid network : sphingosine kinase 2 in immunosuppression, immunopathology, and viral propagation

Abstract

Sphingosine 1-phosphate (S1P) is a bioactive lipid molecule known to regulate diverse cellular functions. S1P is metabolized by the sphingosine kinases (SphK) and S1P lyase (SPL). However, little is known about the role of SphK and SPL in the immune response to viral infections as well as viral pathogenesis. In this study, we demonstrate that during lymphocytic choriomeningitis virus (LCMV) clone 13 infection, a virus known to establish a persistent infection in mice, one SphK isoform, SphK2, functions to limit CD4+ T cell responses, which aids in the establishment of virus-induced immunosuppression and viral persistence. The infection of SphK2-deficient (Sphk2-/-) mice with LCMV resulted in kidney disease and ultimately mortality. Following infection, Sphk2-/- mice were shown to have increased LCMV-specific T cell and neutrophil responses. Depletion of these cells prevented the infection-induced death of SphK2-/- mice, indicating the essential contribution of these cells to the immune pathology. With the use of LCMV epitope-specific TCR transgenic mouse lines in adoptive transfer studies, SphK2 was shown to have intrinsic negative function in CD4+ T cells, but not CD8+ T cells. Importantly, oral treatment of LCMV-infected mice with an SphK2-selective inhibitor increased the number of LCMV-reactive CD4+ and CD8+ T cells and led to the accelerated termination of LCMV persistence. Furthermore, we have identified SphK2 as a cellular factor that is upregulated during influenza A virus (IAV) infection and simultaneously promotes IAV infectivity. Inhibition of SphK2 attenuated IAV replication in vitro and reduced IAV-associated mortality in mouse models. Unlike SphK2, SPL promotes antiviral responses by increasing type I interferon production upon cellular sensing of IAV RNA. Here, we show supporting data for the role of SPL during IAV infection utilizing an SPL-deficient cell line. Overall, these studies indicate a vital role for S1P-metabolizing enzymes during the host response to viral infections.