This application addresses the compelling need to develop new and improved vaccine adjuvants for stimulating protective immunity at mucosal surfaces. The proposal involves a consortium arrangement between the University of Louisville, the University at Buffalo, and the Hauptman-Woodward Institute, and brings together complementary and integrated expertise in vaccine adjuvant research, structural and molecular biology, and induction of mucosal immunity. Studies by this group have succeeded to dissociate useful adjuvant properties from the toxicity of LT-IIb, an AB5-type heat-labile enterotoxin of Escherichia coli. Specifically, the recombinantly expressed B pentameric subunit of LT-IIb (LT-IIb-B5) not only lacks enterotoxicity but, strikingly, can activate the Toll-like receptor (TLR)-2/TLR1 signaling complex and stimulate antibody responses to co-administered vaccine proteins. Proof-of-concept preliminary studies have shown that certain engineered point-substitution mutations in the active region of LT-IIb-B5 enhance its ability to interact with TLR2 and TLR1. The overall objective of this application is to better characterize the physical and functional interaction of LT-IIb-B5 with the TLR2/TLR1 heterodimer, engineer improved versions of LT-IIb-B5 in terms of TLR2/TLR1-mediated adjuvanticity, and develop potential adjuvants through studies in preclinical models of vaccination against oral infection. This will be accomplished through appropriate and innovative molecular biological, structural, and immunological studies outlined in the following four specific aims: 1) To rationally engineer enhanced TLR2-interactive versions of LT-IIb-B5. 2) To structurally characterize the LT-IIb- B5-TLR2/TLR1 interaction using small-angle X-ray scattering (SAXS). 3) To evaluate the engineered LT-IIb-B5 mutants for in vitro TLR2/TLR1-dependent immunostimulatory activities. 4) To determine the ability of LT-IIb-B5 and improved engineered versions thereof to induce protective immunity in vivo. The generated data will form the basis for the long-term goal which is to establish LT-IIb-B5 and improved engineered derivatives as effective adjuvants in vaccine formulations against pathogens which colonize or invade via oral, respiratory, or urogenital mucosal surfaces.
The objective of this application is to rationally engineer novel Toll-like receptor-dependent mucosal adjuvants. These constructs will be evaluated for their capacity to stimulate protective immunity using appropriate preclinical mouse models. The focus of this proposal is on a novel vaccine against periodontitis, an oral inflammatory disease with an impact on systemic health, although the developed mucosal adjuvants can also be used in vaccine formulations against pathogens which colonize or invade via oral, respiratory, or urogenital mucosal surfaces. This work is timely and important given the paucity of safe and effective vaccine adjuvants and the tremendous health impact of infectious diseases.
|Lee, Chang Hoon; Hajishengallis, George; Connell, Terry D (2017) Dendritic Cell-Mediated Mechanisms Triggered by LT-IIa-B5, a Mucosal Adjuvant Derived from a Type II Heat-Labile Enterotoxin of Escherichia coli. J Microbiol Biotechnol 27:709-717|
|Maekawa, T; Kulwattanaporn, P; Hosur, K et al. (2017) Differential Expression and Roles of Secreted Frizzled-Related Protein 5 and the Wingless Homolog Wnt5a in Periodontitis. J Dent Res 96:571-577|
|Maekawa, Tomoki; Briones, Ruel A; Resuello, Ranillo R G et al. (2016) Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3. J Clin Periodontol 43:238-49|
|Mastellos, D C; Ricklin, D; Hajishengallis, E et al. (2016) Complement therapeutics in inflammatory diseases: promising drug candidates for C3-targeted intervention. Mol Oral Microbiol 31:3-17|
|El-Kassas, Seham; Odemuyiwa, Solomon; Hajishengallis, George et al. (2016) Expression and Regulation of Cholecystokinin Receptor in the Chicken's Immune Organs and Cells. J Clin Cell Immunol 7:|
|Hajishengallis, George; Moutsopoulos, Niki M; Hajishengallis, Evlambia et al. (2016) Immune and regulatory functions of neutrophils in inflammatory bone loss. Semin Immunol 28:146-58|
|Hajishengallis, George; Hajishengallis, Evlambia; Kajikawa, Tetsuhiro et al. (2016) Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application. Semin Immunol 28:285-91|
|Hajishengallis, George; Lambris, John D (2016) More than complementing Tolls: complement-Toll-like receptor synergy and crosstalk in innate immunity and inflammation. Immunol Rev 274:233-244|
|Duan, X; Gleason, R C; Li, F et al. (2016) Sex dimorphism in periodontitis in animal models. J Periodontal Res 51:196-202|
|Olsen, Ingar; Hajishengallis, George (2016) Major neutrophil functions subverted by Porphyromonas gingivalis. J Oral Microbiol 8:30936|
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