The cytokine storm is an aggressive immune response characterized by the 
recruitment of inflammatory leukocytes and exaggerated levels of cytokines and 
chemokines at the site of infection. Here we review evidence that cytokine storm 
directly contributes to the morbidity and mortality resulting from influenza 
virus infection and that sphingosine-1-phosphate (S1P) receptor agonists can 
abort cytokine storms providing significant protection against pathogenic human 
influenza viral infections. In experiments using murine models and the human 
pathogenic 2009 influenza viruses, S1P1 receptor agonist alone reduced deaths 
from influenza virus by over 80% as compared to lesser protection (50%) offered 
by the antiviral neuraminidase inhibitor oseltamivir. Optimal protection of 96% 
was achieved by combined therapy with the S1P1 receptor agonist and oseltamivir. 
The functional mechanism of S1P receptor agonist(s) action and the predominant 
role played by pulmonary endothelial cells as amplifiers of cytokine storm 
during influenza infection are described.