The goal of this proposal is to uncover the in vivo mechanisms by which STING (Stimulator of interferon genes) mediates the mucosal vaccine adjuvant activity of cyclic di-GMP (CDG). Protective mucosal immune responses are most effectively induced by mucosal immunization. However, most of the currently approved human vaccines are administered systemically and generally fail to elicit effective mucosal immunity. Live attenuated mucosal vaccines present safety and acceptability issues while purified antigens are generally poor immunogenic when administered by the mucosal route. CDG exhibits potent mucosal immunogenicity thus, has been explored as a promising mucosal vaccine adjuvant. The mechanism by which CDG executes its mucosal adjuvant activity is unknown, which hinders the further development of CDG as an efficacious mucosal adjuvant. STING, also known as MPYS/MITA, is a receptor for CDG. We recently showed that STING-/- mice fail to generate Ag-specific antibody production or TH1-TH2-TH17 T cell response after intranasal CDG/Ag immunization. We further discovered that STING-dependent TNF-a is essential for CDG adjuvant activity in vivo. Intranasal co-administration of CDG/Ag induces immune response in lung and nasal-associated lymphoid tissue (NALT). Here, we will use TNFR1-/-TNFR2-/- and conditional STING-/- mice to dissect the in vivo mechanism of CDG/STING-induced adjuvant activity in lung and NALT. We will adopt both the model Ag OVA and pneumococcal surface protein A (PspA) Ag for our study. Dendritic cells (DC) play a central role in adjuvant activity. We hypothesize that CDG induces STING-dependent inflammatory signals that activate DC directly or indirectly to execute the adjuvant activity of CDG.
Two specific Aims are proposed to carry out this objective.
Aim 1. Determine how STING regulates CDG-induced adjuvant activity in DC.
Aim 2. Determine how TNF-a regulates CDG-induced adjuvant activity. Currently, there is no vaccine formulation containing a mucosal adjuvant approved for human use. The knowledge generated by our studies can help advance the development of CDG as an efficacious mucosal vaccine adjuvant for human use.

Public Health Relevance

Most infectious agents (pathogens) enter the body at mucosal surfaces and therefore mucosal vaccination provides the best protection against pathogen infections. Currently, there is no vaccine formulation containing a mucosal adjuvant approved for human use. In this project, we conduct mechanistic research on a promising mucosal vaccine adjuvant candidate, cyclic di-GMP that can lead to improved safety and efficiency for its future use on human.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI110606-05
Application #
9392476
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Rothermel, Annette L
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Patel, Seema; Blaauboer, Steven M; Tucker, Heidi R et al. (2017) The Common R71H-G230A-R293Q Human TMEM173 Is a Null Allele. J Immunol 198:776-787
Harton, Jonathan; Jin, Lei; Hahn, Amy et al. (2016) Immunological Functions of the Membrane Proximal Region of MHC Class II Molecules. F1000Res 5:
Carroll, Elizabeth C; Jin, Lei; Mori, Andres et al. (2016) The Vaccine Adjuvant Chitosan Promotes Cellular Immunity via DNA Sensor cGAS-STING-Dependent Induction of Type I Interferons. Immunity 44:597-608
Blaauboer, Steven M; Mansouri, Samira; Tucker, Heidi R et al. (2015) The mucosal adjuvant cyclic di-GMP enhances antigen uptake and selectively activates pinocytosis-efficient cells in vivo. Elife 4: