Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid generated intracellularly by the action of sphingosine kinase (SK). Cells that contribute to the extracellular S1P in plasma include platelets, erythrocytes and vascular endothelial cells. One of the functions of S1P is to enhance the integrity of the vascular endothelium. Severe Dengue virus (DENV) infection is associated with increased vascular permeability and thrombocytopenia (low platelet counts), leading to plasma leakage and the potential for haemorrhage and shock. Decreased S1P levels have been reported in serum of DENV patients with lowest levels in patients with severe dengue suggesting that low S1P may contribute to DENV-induced vascular leakage. Studies in our laboratory reveal changes associated with SK activity during DENV infection in vitro. This suggests that the S1P levels are likely to be altered during the course of DENV infection, potentially due to reduced S1P production from DENV-infected cells. In this study we measured the level of serum-S1P in a cohort of DENV patients, in a mouse model of DENV infection and in DENV infected cells in vitro.
Consistent with previous studies S1P levels were lower in a small cohort of DENV positive compared with DENV-negative patients or healthy controls. In contrast, no significant differences were observed in circulating S1P levels in D2Y98P-infected AG129, interferon receptor deficient mice, or in the brain of wild type mice infected intracranial with DENV. Pilot studies in DENV-infected cells suggested no major difference in S1P levels. These results support the published reduction in S1P in the circulation of DENV-infected patients, but suggest this is not reflected in a mouse model of DENV, during infection of the brain or in DENV-infected cells. Further experiments are underway to confirm and extend these findings.
These studies will provide insight on the role of S1P in DENV-induced vascular leakage, the use of S1P as a marker for vascular leakage or as a potential therapeutic target to promote maintenance of vascular integrity during DENV-infection.