Maurizio Del Poeta – Stony Brook University, New-York – USA
An analog of sphingosine-1-phosphate (S1P) that targets S1P receptors 1,3,4, and 5, FTY720 (Gilenya, Novartis), is a treatment of relapsing remitting multiple sclerosis (MS). Recent reports indicate an association between long term exposure to FTY720 and cases of cryptococcal infection. Here, we studied the effect of FTY720 and BAF312 (Mayzent, Novartis), a specific S1P receptor 1 and 5 agonist, in a mouse model of cryptococcal infection. We found that treatment with FTY720, but not with BAF312, leads to decreased survival and increased organ burden in a mouse granuloma model of cryptococcal infection. Both FTY720 and BAF312 cause a profound CD4+ and CD8+ T cell depletion in blood but only treatment with FTY720 leads to cryptococcal reactivation. Treatment with FTY720, but not with BAF312, is associated with disorganization of macrophages, decreased phagocytosis and decreased production of reactive oxygen species by macrophages. The results were validated using S1P3-/- knockout macrophages. The data suggest that FTY720 reactivates cryptococcosis from the granuloma through a S1P3 receptor-mediated mechanism and support the rationale for development of more specific receptor modulators for therapeutic use.
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