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Short duplex RNAs induce potent immunostimulation via Hoogsteen G-G base pairing-mediated dimerization

ABSTRACT: Here we describe a new class of immunostimulatory short duplex RNAs that potently induce production of type I interferon (IFN-I), and particularly IFN-β, in a wide range ofhuman cell types via end-to-end dimerization, direct binding to RIG-I, and activation of the RIG-I/IRF3 pathway. 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 the self-assembly of end-to-end RNA dimers by Hoogsteen G-G base-pairing. The presence of terminal hydroxyl or monophosphate groups, blunt or overhanging ends, or terminal RNA or DNA bases also did not affect their ability to induce IFN-I production. 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 cell lines and in human Lung Chips that mimic organlevel lung pathophysiology. These novel immunostimulatory motifs potentially could be harnessed to create broad-spectrum antiviral therapeutics, but they should be avoided when designing siRNAs to minimize immunological side effects.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Epithelial Cell

DISEASE(S): Severe Acute Respiratory Syndrome

SUBMITTER: Tian Zhang

LAB HEAD: Steven Gygi

PROVIDER: PXD027838 | Pride | 2022-09-01

REPOSITORIES: Pride

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Project description:Background: Type I interferons (IFNs) are essential to the clearance of viral diseases, in part by initiating upregulation of IFN regulated genes (IRGs). A clear distinction between genes upregulated directly by virus and genes upregulated by secondary IFN production has not been made. Here we investigated the genes regulated by IFN-a2b compared to the genes regulated by SARS-CoV infection in ferrets. Methods: We characterized early host immune responses in peripheral blood and lung necropsies of ferrets injected with IFN-a2b or infected with SARS-CoV/Tor 2 strain, using microarray analysis on the Affymetrix platform. Results: We identified a common IRG signature that was upregulated in both SARS-CoV infected ferrets as well as in ferrets injected with IFN-a2b. We also identified unique patterns of gene expression for leukocyte activation, cell adhesion and complement pathways between IFN-a2b injection and SARS-CoV infection. Conclusions: Our results define the effects of IFN-a2b on the immune system of ferrets highlighting genes regulated by IFN during SARS-CoV infection. We have shown the similarities and differences of top funcional gene groups as well as pathways that play key roles in early immune responses in ferrets in response to IFN-a2b or SARS-CoV. Key words: ferret, gene expression, SARS, interferon. Keywords: time course In experiments with IFN-a2b, for peripheral blood, 15 ferrets were randomly allocated to 3 groups: Day 0, 5 ferrets (no IFN injection), day 1, 6 ferrets (injected), and day 2, 4 ferrets (injected). For lung necropsies of injected ferrets with IFN-a2b, we used 12 ferrets in 3 groups: 4 ferrets, day 0 (no IFN injection), 4 ferrets, day 1 (injected) and 4 ferrets, day 2 (injected). Experimental groups for SARS-CoV infection was as follows: For peripheral blood, 3 and 4 ferrets for day 0 (no infection) and day 2 (infection) respectively. For lung neceropsies, a total of 9 ferrets in 3 groups, each with 3 replicates for day 0 (no infection), day 1 (infection) and day 2 (infection).

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Short duplex RNAs induce potent immunostimulation via Hoogsteen G-G base pairing-mediated dimerization

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