An intranasal nanoparticle STING agonist has broad protective immunity against respiratory viruses and variants
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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.
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SciScore for 10.1101/2022.04.18.488695: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Mice and NanoSTING treatment: All studies using animal experiments were reviewed and approved by University of Houston (UH) IACUC.
Field Sample Permit: Influenza A/Hong Kong/2369/2009 (H1N1pdm) was provided by Kwok-Yung Yuen from The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China.Sex as a biological variable We purchased the female 7 to 9-week-old BALB/c mice from Charles River Laboratories. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Cell lines: THP-1 dual cell line (Invivogen) was cultured in a humidified … SciScore for 10.1101/2022.04.18.488695: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Mice and NanoSTING treatment: All studies using animal experiments were reviewed and approved by University of Houston (UH) IACUC.
Field Sample Permit: Influenza A/Hong Kong/2369/2009 (H1N1pdm) was provided by Kwok-Yung Yuen from The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China.Sex as a biological variable We purchased the female 7 to 9-week-old BALB/c mice from Charles River Laboratories. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Cell lines: THP-1 dual cell line (Invivogen) was cultured in a humidified incubator at 37°C and 5% CO2 and grown in RPMI/10% FBS (Corning, NY, USA). THP-1suggested: NoneIsolates of SARS-CoV-2 were obtained from BEI Resources (Manassas, VA) and amplified in Vero E6 cells to create working stocks of the virus. Vero E6suggested: RRID:CVCL_XD71)Homogenized tissue samples were serially diluted in test medium and the virus quantified using an endpoint dilution assay on Vero E6 cells for SARS-CoV-2 and on MDCK cells for influenza virus. MDCKsuggested: CLS Cat# 602280/p823_MDCK_(NBL-2, RRID:CVCL_0422)Experimental Models: Organisms/Strains Sentences Resources For influenza virus animal studies, 8-week-old BALB/c mice were purchased from Charles River Laboratories. BALB/csuggested: RRID:IMSR_ORNL:BALB/cRl)Software and Algorithms Sentences Resources We paired and trimmed the fastq files using Trimmomatic (v 0.39) and aligned them to the Syrian golden hamster genome (MesAur 1.0, ensembl) using STAR (v 2.7.9a). Trimmomaticsuggested: NoneSTARsuggested: NoneWe determined the differential gene expression using DESeq2 (v 1.28.1) package63. DESeq2suggested: (DESeq, RRID:SCR_000154)To perform gene set enrichment analysis, we used a pre-ranked gene list of differentially expressed genes in GSEA software (UC San Diego and Broad Institute). GSEAsuggested: (SeqGSEA, RRID:SCR_005724)Images were scanned using an Aperio ImageScope. ImageScopesuggested: (ImageScope, RRID:SCR_014311)Quantification and statistical analysis: Statistical significance was assigned when P values were <0.05 using GraphPad Prism (v6.07). GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Sample MATLAB code: MATLABsuggested: NoneResults from OddPub: Thank you for sharing your code.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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