Immunostimulatory G, U-containing oligoribonucleotides
Compositions and methods relating to immunostimulatory RNA oligomers are provided. The immunostimulatory RNA molecules are believed to represent natural ligands of one or more Toll-like receptors, including Toll-like receptor 7 (TLR7) and Toll-like receptor 8 (TLR8). The compositions and methods are useful for stimulating immune activation. Methods useful for screening candidate immunostimulatory compounds are also provided.
1. A method of inducing an immune response in a subject to an antigen, the method comprising:
administering a composition comprising an isolated single-stranded RNA (ssRNA) G,U-rich oligoribonucleotide 5-40 nucleotides long having at least 80 percent G and U to a subject via a route of administration selected from the group consisting of mucosal, oral, intranasal, sublingual, ocular, vaginal, rectal, buccal, and by inhalation, wherein the G,U-rich oligoribonucleotide is free of CpG dinucleotide, wherein the administration requires cationic lipids, wherein the ssRNA is a ligand of Toll-like receptor 7 (TLR7) or TLR8, wherein the composition further comprises an antigen, and wherein the composition comprises an effective amount of the ssRNA G,U-rich oligoribonucleotide to induce an immune response to the antigen.
2. The method of claim 1 , wherein TLR7- mediated activation by the ssRNA G,U-rich oligoribonucleotide leads to IFN-α secretion from plasmacytoid precursor dendritic cells (pDCs) and TLR8- mediated activation by the ssRNA G,U-rich oligoribonucleotide leads to TNF-α secretion from monocytes.
3. The method of claim 1 , wherein the antigen is selected from the group consisting of an allergen, an antigen of a bacterium, an antigen of a virus, an antigen of a fungus, an antigen of a parasite, and a cancer antigen.
4. The method of claim 1 , wherein the antigen comprises a peptide or a polypeptide.
5. The method of claim 1 , wherein the antigen comprises a cell.
6. The method of claim 1 , wherein the composition is administered to the subject more than once.
7. The method of claim 1 , wherein the immune response comprises a Th1 immune response.
8. The method of claim 1 , wherein the ssRNA G,U-rich oligoribonucleotide is a ligand of both TLR7 and TLR8.