Bioengineering Bacterially Derived Immunomodulants: A Therapeutic Approach to Inflammatory Bowel Disease

• Published in: ACS nano Vol. 11; no. 10; pp. 9650 - 9662
• Main Authors: Herrera Estrada, Lina, Wu, Huixia, Ling, Kevin, Zhang, Guikai, Sumagin, Ronen, Parkos, Charles A, Jones, Rheinallt M, Champion, Julie A, Neish, Andrew S
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24.10.2017
• Subjects: Animals; Bacterial Proteins - chemical synthesis; Bacterial Proteins - chemistry; Bacterial Proteins - therapeutic use; Colitis - drug therapy; Disease Models, Animal; Humans; Immunomodulation; Inflammation - drug therapy; Inflammatory Bowel Diseases - drug therapy; Mice; Mice, Inbred C57BL; Nanoparticles - chemistry; Nanoparticles - therapeutic use; Particle Size; Protein Engineering; Rats; anti-inflammatory; nanoparticles; colitis; intracellular delivery; effector protein
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.7b03239

Bacterial enteric pathogens have evolved efficient mechanisms to suppress mammalian inflammatory and immunoregulatory pathways. By exploiting the evolutionary relationship between the gut and pathogenic bacteria, we have developed a potential mucosal therapeutic. Our findings suggest that engineered preparations of the Salmonella acetyltransferase, AvrA, suppress acute inflammatory responses such as those observed in inflammatory bowel disease (IBD). We created 125 nm diameter cross-linked protein nanoparticles directly from AvrA and carrier protein to deliver AvrA in the absence of Salmonella. AvrA nanoparticles are internalized in vitro and in vivo into barrier epithelial and lamina propria monocytic cells. AvrA nanoparticles inhibit inflammatory signaling and confer cytoprotection in vitro, and in murine colitis models, we observe decreased clinical and histological indices of inflammation. Thus, we have combined naturally evolved immunomodulatory proteins with modern bioengineering to produce AvrA nanoparticles, a potential treatment for IBD.