TGF-beta1 induces transendothelial migration of the pathogenic fungus Sporothrix schenckii by a paracellular route involving extracellular matrix proteins.

Sporotrichosis, a mycosis caused by Sporothrix schenckii, is characterized by lymphocutaneous lesions. In immunocompromised hosts, this fungus may invade the bloodstream and disseminate to other tissues, such as lung and bone. Our group previously showed that S. schenckii yeasts adhere to endothelial monolayers and that this interaction is modulated by cytokines. Using 3.0 mum-pore culture inserts, the present work shows that transforming growth factor (TGF)-beta1 led to a 80+/-26 % increase in fungal migration across endothelial monolayers and inhibited fungus internalization by 55+/-23.5 %, when compared to untreated cells. The major surface endothelial molecules recognized by S. schenckii were not modulated by TGF-beta1. These data suggested that a paracellular route is preferentially used by S. schenckii during the transmigration of cultured endothelial cells. It was further observed that TGF-beta1 increased the subendothelial matrix exposure and that anti-fibronectin (anti-FN) and anti-laminin (anti-LM) antibodies abolished the increase in S. schenckii association with endothelial monolayers induced by TGF-beta1. These antibodies also inhibited (38.2+/-4.29 % and 50.8+/-17.3 %, respectively) the adhesion of S. schenckii to freshly prepared native endothelial matrices. Furthermore, transendothelial migration of S. schenckii was blocked by anti-FN and anti-LM antibodies. These data indicate that TGF-beta1-induced S. schenckii adhesion to endothelial monolayers results from the increased exposure of the subendothelial extracellular matrix and that this event may contribute to the enhancement of transendothelial migration.