An intranasal nanoparticle STING agonist has broad protective immunity against respiratory viruses and variants
Open Access
- 19 April 2022
- preprint content
- research article
- Published by Cold Spring Harbor Laboratory
Abstract
Respiratory viral infections, especially Influenza (endemic) or SARS-CoV-2 (pandemic since 2020), cause morbidity and mortality worldwide. Despite remarkable progress in the development and deployment of vaccines, they are clearly impacted by the rapid emergence of viral variants. The development of an off-the-shelf, effective, safe, and low-cost drug for prophylaxis against respiratory viral infections is a major unmet medical need. Here, we developed NanoSTING, a liposomally encapsulated formulation of the endogenous STING agonist, 2’-3’ cGAMP, to function as an immunoantiviral. NanoSTING rapidly activates the body’s innate immune system to facilitate a broad-spectrum antiviral response against SARS-CoV-2 and influenza variants in hamsters and mice. We demonstrate that a single intranasal dose of NanoSTING can: (1) treat infections throughout the respiratory system and minimize clinical symptoms, (2) protect against highly pathogenic strains of SARS-CoV-2 (alpha and delta), (3) provide durable protection against reinfection from the same strains without the need for retreatment, (4) prevent transmission of the highly infectious SARS-CoV-2 Omicron strain, and (5) provide protection against both oseltamivir-sensitive and resistant strains of influenza. Mechanistically, administration of NanoSTING rapidly upregulated interferon-stimulated and antiviral pathways in both the nasal turbinates and lung. Our results support using NanoSTING as a thermostable, immunoantiviral with broad-spectrum antiviral properties making it appealing as a therapeutic for prophylactic or early post-exposure treatment.Keywords
This publication has 63 references indexed in Scilit:
- GADD45 proteins inhibit HIV-1 replication through specific suppression of HIV-1 transcriptionVirology, 2016
- Ancient Origin of cGAS-STING Reveals Mechanism of Universal 2′,3′ cGAMP SignalingMolecular Cell, 2015
- DDX60 Is Involved in RIG-I-Dependent and Independent Antiviral Responses, and Its Function Is Attenuated by Virus-Induced EGFR ActivationCell Reports, 2015
- Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2Genome Biology, 2014
- Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon PathwayScience, 2013
- Low‐dose oral interferon alpha as prophylaxis against viral respiratory illness: a double‐blind, parallel controlled trial during an influenza pandemic yearInfluenza and Other Respiratory Viruses, 2013
- Global Transmission of Oseltamivir-Resistant InfluenzaThe New England Journal of Medicine, 2009
- Influenza A Virus Inhibits Type I IFN Signaling via NF-κB-Dependent Induction of SOCS-3 ExpressionPLoS Pathogens, 2008
- A Recombinant Influenza A Virus Expressing anRNA-Binding-Defective NS1 Protein Induces High Levels of BetaInterferon and Is Attenuated inMiceJournal of Virology, 2003
- Distribution of intranasal instillations in mice: effects of volume, time, body position, and anesthesiaAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2002