Self-assembling short immunostimulatory duplex RNAs with broad-spectrum antiviral activity.

Autor:	Si L; Wyss Institute for Biologically Inspired Engineering, Harvard University, CLSB5, 3 Blackfan Circle, Boston, MA 02115, USA., Bai H; Wyss Institute for Biologically Inspired Engineering, Harvard University, CLSB5, 3 Blackfan Circle, Boston, MA 02115, USA., Oh CY; Wyss Institute for Biologically Inspired Engineering, Harvard University, CLSB5, 3 Blackfan Circle, Boston, MA 02115, USA., Jiang A; Wyss Institute for Biologically Inspired Engineering, Harvard University, CLSB5, 3 Blackfan Circle, Boston, MA 02115, USA.; Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA., Hong F; Wyss Institute for Biologically Inspired Engineering, Harvard University, CLSB5, 3 Blackfan Circle, Boston, MA 02115, USA., Zhang T; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Ye Y; Department of Genetics, Harvard Medical School, Boston, MA 02155, USA., Jordan TX; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Logue J; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., McGrath M; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Belgur C; Wyss Institute for Biologically Inspired Engineering, Harvard University, CLSB5, 3 Blackfan Circle, Boston, MA 02115, USA., Calderon K; Wyss Institute for Biologically Inspired Engineering, Harvard University, CLSB5, 3 Blackfan Circle, Boston, MA 02115, USA., Nurani A; Wyss Institute for Biologically Inspired Engineering, Harvard University, CLSB5, 3 Blackfan Circle, Boston, MA 02115, USA., Cao W; Wyss Institute for Biologically Inspired Engineering, Harvard University, CLSB5, 3 Blackfan Circle, Boston, MA 02115, USA., Carlson KE; Wyss Institute for Biologically Inspired Engineering, Harvard University, CLSB5, 3 Blackfan Circle, Boston, MA 02115, USA., Prantil-Baun R; Wyss Institute for Biologically Inspired Engineering, Harvard University, CLSB5, 3 Blackfan Circle, Boston, MA 02115, USA., Gygi SP; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Yang D; Regional Biocontainment Laboratory, The University of Tennessee Health Science Center, Memphis, TN 38105, USA., Jonsson CB; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38105, USA., tenOever BR; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Frieman M; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Ingber DE; Wyss Institute for Biologically Inspired Engineering, Harvard University, CLSB5, 3 Blackfan Circle, Boston, MA 02115, USA.; Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA 02139, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2022 Sep 13; Vol. 29, pp. 923-940. Date of Electronic Publication: 2022 Aug 24.
DOI:	10.1016/j.omtn.2022.08.031
Abstrakt:	The current coronavirus disease 2019 (COVID-19) pandemic highlights the need for broad-spectrum antiviral therapeutics. Here we describe a new class of self-assembling immunostimulatory short duplex RNAs that potently induce production of type I and type III interferon (IFN-I and IFN-III). These RNAs require a minimum of 20 base pairs, lack any sequence or structural characteristics of known immunostimulatory RNAs, and instead require a unique sequence motif (sense strand, 5'-C; antisense strand, 3'-GGG) that mediates end-to-end dimer self-assembly. The presence of terminal hydroxyl or monophosphate groups, blunt or overhanging ends, or terminal RNA or DNA bases did not affect their ability to induce IFN. Unlike previously described immunostimulatory small interfering RNAs (siRNAs), their activity is independent of Toll-like receptor (TLR) 7/8, but requires the RIG-I/IRF3 pathway that induces a more restricted antiviral response with a lower proinflammatory signature compared with immunostimulant poly(I:C). Immune stimulation mediated by these duplex RNAs results in broad-spectrum inhibition of infections by many respiratory viruses with pandemic potential, including severe acute respiratory syndrome coronavirus (SARS-CoV)-2, SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), human coronavirus (HCoV)-NL63, and influenza A virus in cell lines, human lung chips that mimic organ-level lung pathophysiology, and a mouse SARS-CoV-2 infection model. These short double-stranded RNAs (dsRNAs) can be manufactured easily, and thus potentially could be harnessed to produce broad-spectrum antiviral therapeutics. Competing Interests: D.E.I. is a founder, board member, SAB chair, and equity holder in Emulate Inc. D.E.I., L.S., H.B., C.O., and R.P. are inventors on relevant patent applications held by Harvard University. (© 2022 The Author(s).)
Databáze:	MEDLINE
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