Project Summary The GEF-H1-IKKε-IRF5 signaling axis is an essential pathway for the recognition of peptidoglycans and enables host defense responses to cope with intracellular pathogens such as Listeria monocytogenes. Macrophages contain a reservoir of inactive GEF-H1 bound to microtubules that is activated by dephosphorylation to form signaling platforms for the control of innate and adaptive immunity. The GEF-H1 pathway is well positioned to allow the intracellular detection of cell-invasive pathogens. As many pathogens have developed mechanisms for intracellular survival and immune avoidance, the GEF-H1 pathway may have evolved to allow critical immune detection of microbial effectors that target cytoskeletal components. However, it is unclear how microbial effectors and pattern recognition receptors regulate microtubule dynamics for the activation of GEF-H1. This application seeks support for studies designed to understand the key role of GEF-H1 in microbial detection and to define the precise requirements for the activation of immune responses through microtubule based microbial pattern recognition.