Modulation of Notch signaling by intracellular bacterial toxins (610.3)

Abstract

The Notch signaling pathway has recently been recognized as a critical signaling pathway in macrophages. This study examines how Notch signaling functions in the context of infectious disease as well as how contrasting intracellular bacterial toxins modify this pathway. In this work, we investigate how the Notch signaling pathway is altered in macrophages by Bacillus anthracis edema toxin (ET) and Clostridium difficile toxin B (TcdB). In preliminary studies, ET was found to activate and augment Notch signaling in macrophages through a mechanism involving transducin‐like enhancer of split (TLE) and recombinant recognition sequence binding protein at the Jκ site (RBP‐J). Because ET, an immunosuppressive toxin, activates Notch signaling in macrophages, we hypothesized that TcdB, an inflammation stimulating toxin, may have an alternative effect on this signaling pathway. To address this possibility, the Notch signaling pathway was examined in primary macrophages exposed to TcdB, and results from these studies found that Notch signaling was suppressed by TcdB. Further analyses have suggested that the TcdB induced suppression of Notch signaling is through a mechanism involving the stimulation of interferon signaling. These results provide insight into mechanisms utilized by disparate bacterial toxins to modify Notch signaling in macrophages.