Commensal bacteria-derived nanoparticles for correcting gut inflammation

About This Grant

PROJECT SUMMARY/ ABSTRACT: Currently, the therapeutic options available to individuals with inflammatory bowel disorder (IBD) are limited to small molecule drug and biologics with high toxicity and off-target effects. IBD (and gut dysbiosis) have been directly linked to a plethora of metabolic, neural, allergic and autoimmune diseases, further emphasizing the need for effective and safe therapy. Interestingly, gut dysbiosis is distinguished by deficiency in IL-10 in the inflamed areas. Moreover, there are defects in immune regulation affecting regulatory T cell (Treg) activity and IL-10 signaling. Tregs can inhibit inflammatory immune cells such as M1 macrophages and Th17 cells via secretion of anti-inflammatory cytokines (e.g. IL-10). Moreover, Tregs specific for a disease relevant antigen have been shown to be advantageous over polyclonal Tregs. Traditionally, IBD has not been considered an antigen-specific, inflammatory disease. However, groups have shown that there is generation of monoclonal antibodies to epitopes derived from host proteins (e.g. tropomyosin), as well as antibodies against gut pathogens. Ostensibly, localized generation of antigen-specific Tregs can curtail and counter gut dysbiosis. The immunomodulatory biomaterials lab at UF is currently engineering nanoparticles (NPs) from a polymer derived from commensal bacteroides - Polysaccharide A (PSA). PSA is found on the capsule of the commensal bacterium B. fragilis and directly interacts with antigen presenting cells (APCs), particularly dendritic cells (DCs) to direct and maintain the balance of immunity in the gut. Relevant to this application, we have shown that purified PSA can be used to generate nanoparticles with strong and specific activation of TLR2 on DCs, and robust downstream production of interleukin (IL)-10 from regulatory T cells. Here, we propose to develop an off-the-shelf-approach for ulcerative colitis (UC), which involves glycosylated antigen-loaded PSA nanoparticles (NPs) to drive tolerogenic DCs in the mucosal epithelium and induce effective numbers of UC specific-Tregs to ameliorate UC. Our long-term goal is to develop a modular, easily administrable, tolerance-inducing platform for treatment of gut dysbiosis. The overall objective of this R21 proposal is to engineer glycosylated antigen-loaded PSA NPs to attenuate UC in a murine model, and investigate the extent of immune modulation following oral administration. Our central hypothesis is that upon oral delivery, these engineered NPs will resist digestive tract degradation, target inflammation in the intestine and interact with innate immune cells in these areas to induce specific, anti-inflammatory responses and attenuation of gut dysbiosis. The overall objective of this R21 proposal is addressed by the following two specific aims: 1) Engineer glycosylated antigen-loaded PSA NPs and characterize their physico-chemical properties, in vitro modulatory capacity and biodistribution following oral delivery; 2) Evaluate the therapeutic capacity of PSA NPs in an OVA-DSS murine model of Colitis. The proposed research is novel and innovative due to the simplicity of its generation and administration to the patient, and huge potential as a therapeutic agent for IBD.