INTERFERON-ALPHA INHIBITS A SRC-MEDIATED PATHWAY NECESSARY FOR SHIGELLA-INDUCED CYTOSKELETAL REARRANGEMENTS IN EPITHELIAL-CELLS

Shigella flexneri, the causative agent of bacillary dysentery, has the ability to enter nonphagocytic cells. The interferon (IFN) family of cytokines was found to inhibit Shigella invasion of cultured epithelia l cells. We show here that IFN-alpha inhibits a Src-dependent signalin g cascade triggered by Shigella that leads to the reorganization of th e host cell cytoskeleton. Immunofluorescence studies showed that IFN-a lpha inhibits Shigella-induced actin polymerization required for bacte rial entry into cells. Phosphorylation of cortactin, a Src-substrate s pecifically tyrosyl-phosphorylated during Shigella entry, was inhibite d by IFN-alpha. Overexpression of a dominant interfering form of pp60c -src led to inhibition of Shigella-induced cytoskeletal rearrangements and decreased cortactin phosphorylation indicating a role for Src in Shigella entry. Also, Shigella uptake in cells that expressed constitu tively active Src was unaffected by IFN-alpha treatment. We conclude t hat Src kinase activity is necessary for Shigella invasion of epitheli al cells and that IFN-alpha inhibits this Src-dependent signaling path way.