Engineering Salmonella Effector Protein as an Inflammatory Bowel Disease Therapeutic

Bacterial pathogens have evolved effector proteins to suppress mammalian inflammatory and immunoregulatory pathways. One such protein, AvrA from Salmonella, is an acetyltransferase that inhibits inflammatory JNK and NF-kB signaling without inducing apoptosis. We have engineered AvrA protein nanoparticles to deliver AvrA intracellularly in the absence of the Salmonella secretion system. AvrA nanoparticles are internalized in vitro and in vivo into epithelial and monocytic cells. They inhibit inflammatory signaling and confer cytoprotection in vitro. In two murine colitis models, we observe decreased clinical and histological indices of inflammation for either preventative or therapeutic dosing via transrectal instillation. To implement AvrA nanoparticles as a clinically viable treatment for IBD with access to the entire intestinal tract and improved patient compliance, an oral formulation was designed. AvrA nanoparticles were encapsulated into microparticles using a microfluidic device. The microparticles protected their protein cargo in the gastric compartment and released the nanoparticles for intracellular delivery in vitro and in vivo. Prevention of colitis symptoms was observed following oral delivery of AvrA nanoparticles in microparticles. This work illustrates the potential therapeutic benefits of bacterial pathogen effectors when delivered outside the context of infection.

Co-Authors: Kevin Ling, Lina Herrera Estrada, Huixia Wu, Andrew S Neish, and Julie Champion