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

Autor: Si L; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Bai H; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Oh CY; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Zhang T; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Hong F; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Jiang A; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.; Vascular Biology Program and Department of Surgery, Boston Children's Hospital and 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, 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, Boston, MA 02115, USA., Nurani A; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Cao W; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Prantil-Baun R; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Gygi SP; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Powers RK; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Frieman M; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., tenOever BR; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Ingber DE; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.; Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA 02139, USA.; Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2021 Nov 22. Date of Electronic Publication: 2021 Nov 22.
DOI: 10.1101/2021.11.19.469183
Abstrakt: The current 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), in a wide range of human cell types. These RNAs require a minimum of 20 base pairs, lack any sequence or structural characteristics of known immunostimulatory RNAs, and instead require a unique conserved sequence motif (sense strand: 5'-C, antisense strand: 3'-GGG) that mediates end-to-end dimer self-assembly of these RNAs by Hoogsteen G-G base-pairing. 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 siRNAs, their activity is independent of TLR7/8, but requires the RIG-I/IRF3 pathway that induces a more restricted antiviral response with a lower proinflammatory signature compared with 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 SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A, as well as the common cold virus HCoV-NL63 in both cell lines and human Lung Chips that mimic organ-level lung pathophysiology. These short dsRNAs can be manufactured easily, and thus potentially could be harnessed to produce broad-spectrum antiviral therapeutics at low cost.
Databáze: MEDLINE