The project goal of this U01 application is to develop a combination of synthetic immunostimulatory agents that maximizes host resistance to potentially lethal microbial agents. Most pathogens important for biodefense are first encountered at mucosal or epithelial sites in the respiratory tree or the gastrointestinal tract. Many microbial agents display ligands that activate one or more Toll-like receptors (TLRs). Dendritic cells (DCs) at mucosal sites play a crucial role in immune responses against infections by sensing microbial invasion through TLRs. However, DC activation by microbial agents may be compromised at the mucosal surfaces of normal people, because of a tolerogenic immune environment. Based upon our preliminary experiments, we believe that this local immune deficit can be overcome by delivering to mucosal surfaces an optimized combination of TLR ligands, together with a potentiator of TLR signaling. Our proposed experiments will focus on activators of TLR7 and TLR9, which are coexpressed by DCs. In some cases, the TLR ligands will be combined with synthetic inhibitors of IMP dehydrogenase (IMPDH), which have been shown to potentiate TLR signaling by inducing interferon regulatory factors. The proposed experiments also will exploit several cell and animal model systems that should predict clinical activity. This project has three development milestones: 1. To compare novel synthetic activators of TLR7 and 9, with a cell nonspecific activator of TLR2, for their abilities to induce cytokine and co-stimulatory molecule synthesis by murine and human cells, used alone and in combination with IMPDH inhibitors. 2. To analyze the effects of the synthetic TLR ligands and IMPDH inhibitors on innate and adaptive immunity in animals after mucosal and systemic administration. 3. To test the efficacies of the optimized drug combinations to protect mice from lethal bacterial and viral infections. When complete, these experiments will deliver a rationally conceived and thoroughly evaluated product for clinical testing.
| Wu, Christina C N; Crain, Brian; Yao, Shiyin et al. (2014) Innate immune protection against infectious diseases by pulmonary administration of a phospholipid-conjugated TLR7 ligand. J Innate Immun 6:315-24 |
| Hayashi, Tomoko; Gray, Christine S; Chan, Michael et al. (2009) Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7. Proc Natl Acad Sci U S A 106:2764-9 |
| Hayashi, Tomoko; Cottam, Howard B; Chan, Michael et al. (2008) Mast cell-dependent anorexia and hypothermia induced by mucosal activation of Toll-like receptor 7. Am J Physiol Regul Integr Comp Physiol 295:R123-32 |
| Wu, Christina C N; Sabet, Mojgan; Hayashi, Tomoko et al. (2008) In vivo efficacy of a phosphodiester TLR-9 aptamer and its beneficial effect in a pulmonary anthrax infection model. Cell Immunol 251:78-85 |
| Wu, Christina C N; Hayashi, Tomoko; Takabayashi, Kenji et al. (2007) Immunotherapeutic activity of a conjugate of a Toll-like receptor 7 ligand. Proc Natl Acad Sci U S A 104:3990-5 |
| Sabet, Mojgan; Cottam, Howard B; Guiney, Donald G (2006) Modulation of cytokine production and enhancement of cell viability by TLR7 and TLR9 ligands during anthrax infection of macrophages. FEMS Immunol Med Microbiol 47:369-79 |
| Takabayshi, Kenji; Corr, Maripat; Hayashi, Tomoko et al. (2006) Induction of a homeostatic circuit in lung tissue by microbial compounds. Immunity 24:475-87 |
| Jin, Guangyi; Wu, Christina C N; Carson, Dennis A et al. (2006) Guanosine analog in the pyrido[2,3-d]pyrimidine ring system as a potential toll-like receptor agonist. Nucleosides Nucleotides Nucleic Acids 25:1391-7 |
| Datta, Sandip K; Okamoto, Sharon; Hayashi, Tomoko et al. (2006) Vaccination with irradiated Listeria induces protective T cell immunity. Immunity 25:143-52 |
| Lee, Jongdae; Wu, Christina C N; Lee, Ki Jeong et al. (2006) Activation of anti-hepatitis C virus responses via Toll-like receptor 7. Proc Natl Acad Sci U S A 103:1828-33 |
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