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

• Type of Material: Article
• Authors: Lina Herrera Estrada, Georgia Institute of Technology; Huixia Wu, Emory University; Kevin Ling, Georgia Institute of Technology; Guikai Zhang, Emory University; Ronen Suinagin, Emory University; Charles A. Parkos, Emory University; Rheinallt Jones, Emory University; Julie A. Champion, Georgia Institute of Technology; Andrew Neish, Emory University
• Language: English
• Date: 2017-10-01
• Publisher: AMER CHEMICAL SOC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 American Chemical Society
• Final Published Version (URL): http://dx.doi.org/10.1021/acsnano.7b03239
• Title of Journal or Parent Work: ACS NANO
• Volume: 11
• Issue: 10
• Start Page: 9650
• End Page: 9662
• Grant/Funding Information: This work was supported by the National Institutes of Health (1R56 DK095074-01A1), the Kenneth Rainin Foundation (10H2), and the Crohn’s and Colitis Foundation of America (274694).
• Keywords: Materials Science, Multidisciplinary; IMMUNE; Nanoscience & Nanotechnology; nanoparticles; SALMONELLA PROTEIN; Science & Technology - Other Topics; Technology; EPITHELIAL-CELLS; Chemistry; anti-inflammatory; SIGNALING PATHWAY; effector protein; intracellular delivery; INTRACELLULAR DELIVERY; Materials Science; NANOPARTICLES; colitis; Chemistry, Physical; Physical Sciences; Chemistry, Multidisciplinary; Science & Technology; DRUG-DELIVERY; MOUSE MODELS; PATHOGENESIS; COLITIS

Abstract

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.