Combination of sphingosine-1-phosphate receptor 1 (S1PR1) agonist and antiviral drug: a potential therapy against pathogenic influenza virus

摘要

The pandemic 2009 infuenza A H1N1 virus is associated with signifcant mortality. Targeting S1PR1,which is known to modulate the immune response, provides protection against pathogenic infuenzavirus. The functional role and molecular mechanism of S1PR1 were analysed by generating inducibleendothelial cell-specifc S1PR1 knockout mice and assessing the therapeutic efcacy of the selectiveS1PR1 agonist CYM5442 against acute lung injury (ALI) induced by the 2009 infuenza A H1N1virus. Immune-mediated pulmonary injury is aggravated by the absence of endothelial S1PR1 andalleviated by treatment with CYM-5442, suggesting a protective function of S1PR1 signaling duringH1N1 infection. S1PR1 signaling does not afect viral clearance in mice infected with infuenza.Mechanistically, the MAPK and NF-kB signaling pathways are involved in the ALI mediated by S1PR1in infected mice. Combined administration of the S1PR1 agonist CYM-5442 and the antiviral drugoseltamivir provides maximum protection from ALI. Our current study provides insight into themolecular mechanism of S1PR1 mediating the ALI induced by H1N1 infection and indicates that thecombination of S1PR1 agonist with antiviral drug could potentially be used as a therapeutic remedy forfuture H1N1 virus pandemics.