Advances in defining the intracellular recognition systems for microbial nucleic acids and membrane components hold opportunities for directed immune therapies of malignancies and intervention in chronic inflammatory and autoimmune diseases processes.

The newly identified GEFH1-IKKε-IRF5 signaling pathway in macrophages is essential for the detection of peptidoglycans and activation of host defense responses against intracellular bacterial and viral pathogens. This microtubule-based recognition system induces a unique transcriptional response program independent of Toll-like and NOD-like receptor signaling. Beyond directing anti-microbial host defense, the outcomes of our experiments also have broader implications for anti-tumor immunity. Microtubule destabilization with subsequent GEFH1 activation identified an alternate intracellular axis for dendritic cells maturation in which GEFH1 is essential for protective anti-tumor immunity.

Cyclic di-guanylate monophosphate is a transcriptional regulator in bacteria that activates the intracellular DNA sensor stimulator of interferon genes (STING), encoded by Tmem173. Our characterization of the function of interferon regulatory factors controlled by the STING signaling axis for adaptive T cell control will aid in the elucidation of disease mechanisms that are initiated by host or pathogen DNA recognition in the cytosol.