The need to develop new vaccines against mucosal pathogens has compelled a search for adjuvants that can effectively stimulate mucosal immunity to vaccine proteins, most of which are poor immunogens. Toll- like receptors (TLRs) and gangliosides are considered """"""""adjuvant receptors"""""""" because their interaction with certain classes of noxious microbial molecules generates potent immunomodulatory signals in antigen- presenting cells (APCs) that mobilize adaptive immunity. An ideal adjuvant should thus stimulate adjuvant receptors without, however, inducing toxic effects. This proposal will investigate the adjuvant activities of a novel ganglioside-binding TLR2 agonist, recently identified by our group. The molecule under investigation is the pentameric B subunit of a unique E. coli enterotoxin, designated Type Mb(LT-llb) and quite different from Type I enterotoxins such as cholera toxin. In contrast to the intact toxin, the B subunit (designated LT- llb-B) induces TLR2-dependent activation of transcription factor NF-KB, which plays a central role in the induction of immunoregulatory cytokines and costimulatory molecules on APCs, such as dendritic cells. The overall hypothesis is that LT-llb-B exhibits immunomodulatory activity, which requires the cooperation of GD1a ganglioside and TLR2, promotes antigen-presenting cell function, and induces mucosal immunity. We thus aim to elucidate the immunomodulatory mechanisms of LT-llb-B and demonstrate its mucosal adjuvanticity. Specifically, using immunological, biophysical, and cell imaging techniques, we will determine cooperative interactions between gangliosides and TLR2 in response to LT-llb-B, and the importance of these interactions in upregulating dendritic cell-mediated functional costimulation to CD4+T cells. Moreover, it will be determined if these adjuvant mechanisms of LT-llb-B correlate with induction of mucosal adjuvant activity in vivo. The proposed studies are supported by a plethora of preliminary findings and are facilitated by the availability of (a) engineered wild-type and single point substitution mutants of LT-II molecules, (b) model cell systems where expression of receptors of interest is manipulated and (c) a well-established mouse mucosal immunization model. Using these models and state-of-the-art interdisciplinary techniques, the generated data will form the basis for our ultimate objective which is to establish LT-llb-B as a safe and effective adjuvant in vaccine formulations against oral or other mucosal pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE017138-05
Application #
7755037
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Burgoon, Penny W
Project Start
2006-02-01
Project End
2010-09-14
Budget Start
2010-02-01
Budget End
2010-09-14
Support Year
5
Fiscal Year
2010
Total Cost
$346,100
Indirect Cost
Name
University of Louisville
Department
Dentistry
Type
Schools of Dentistry
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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
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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
Hajishengallis, George; Lamont, Richard J (2016) Dancing with the Stars: How Choreographed Bacterial Interactions Dictate Nososymbiocity and Give Rise to Keystone Pathogens, Accessory Pathogens, and Pathobionts. Trends Microbiol 24:477-89
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; 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
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

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