Broad-Spectrum Antiviral Activity of Influenza A Defective Interfering Particles against Respiratory Syncytial, Yellow Fever, and Zika Virus Replication In Vitro

Viruses, Journal Year: 2023, Volume and Issue: 15(9), P. 1872 - 1872

Published: Sept. 4, 2023

New broadly acting and readily available antiviral agents are needed to combat existing emerging viruses. Defective interfering particles (DIPs) of influenza A virus (IAV) regarded as promising options for the prevention treatment IAV infections. Interestingly, DIPs also inhibit unrelated viral infections by stimulating innate immunity. Here, we tested ability suppress respiratory syncytial, yellow fever Zika in vitro. In human lung (A549) cells, DIP co-infection inhibited replication spread all three contrast, observed no activity Vero which deficient production interferon (IFN), demonstrating its importance effect. Further, A549 an enhanced type-I type-III IFN response upon that appears explain potential DIPs. Finally, a lack presence Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib was detected. This revealed dependency on JAK/signal transducers activators transcription (STAT) signaling pathway. Overall, this study supports notion may be used broad-spectrum antivirals treat with variety IFN-sensitive viruses, particularly

Language: Английский

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An intranasal nanoparticle STING agonist protects against respiratory viruses in animal models

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 18, 2024

Abstract Respiratory viral infections cause morbidity and mortality worldwide. Despite the success of vaccines, vaccination efficacy is weakened by rapid emergence variants with immunoevasive properties. The development an off-the-shelf, effective, safe therapy against respiratory thus desirable. Here, we develop NanoSTING, a nanoparticle formulation endogenous STING agonist, 2′−3′ cGAMP, to function as immune activator demonstrate its safety in mice rats. A single intranasal dose NanoSTING protects pathogenic strains SARS-CoV-2 (alpha delta VOC) hamsters. In transmission experiments, reduces Omicron VOC naïve also oseltamivir-sensitive oseltamivir-resistant influenza mice. Mechanistically, upregulates locoregional interferon-dependent interferon-independent pathways mice, hamsters, well non-human primates. Our results implicate broad-spectrum for controlling virus infection.

Language: Английский

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Defective Interfering Particles with Broad-Acting Antiviral Activity for Dengue, Zika, Yellow Fever, Respiratory Syncytial and SARS-CoV-2 Virus Infection

Microbiology Spectrum, Journal Year: 2022, Volume and Issue: 10(6)

Published: Nov. 29, 2022

More than 100 arboviruses, almost all of which have an RNA genome, cause disease in humans. viruses are causing unprecedented health system challenges worldwide, many with little or no specific therapies vaccines available. Certain species mosquito can carry dengue virus (DENV), Zika (ZIKV) and yellow fever (YFV), where co-infection these has occurred. Here, we found that purified synthetic defective interfering particles (DIPs) derived from DENV type 2 (DENV-2) strongly suppressed replication the aforementioned viruses, respiratory syncytial (RSV) also novel emerging SARS-CoV-2 human cells. DIPs produced bioreactors, by column chromatography, concentrated virus-like about half diameter a typical particle, but similar ratios viral structural proteins envelope capsid. Overall, DIP-treated cells inhibited DENV, ZIKV, YFV, RSV, at least 98% mechanisms included interferon (IFN)-dependent cellular antiviral responses.

Language: Английский

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Exploring the mechanisms of interference, persistence and antiviral potential of defective interfering particles

Discover Viruses., Journal Year: 2025, Volume and Issue: 2(1)

Published: Jan. 17, 2025

Defective interfering particles (DIPs) were first described by Preben von Magnus as a non-infectious form of influenza virus arising due to undiluted passages the in embryonated eggs. DIPs are characterized internal deletions viral genome, interference with standard replication, attenuation cytopathic effects and persistence. Even though DIP-mediated host cell persistence have been reported both experimental natural infections, processes involved modifying or influencing fate infection poorly understood. In this review, properties DIPs, mechanisms modulation disease outcomes their possibilities towards an antiviral approach highlighted.

Language: Английский

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Antivirotics based on defective interfering particles: emerging concepts and challenges

Frontiers in Cellular and Infection Microbiology, Journal Year: 2025, Volume and Issue: 15

Published: Feb. 24, 2025

Viruses are obligate parasites, that use the host's internal metabolic systems for their own reproduction. This complicates search molecular targets to prevent spread of viral infection without disrupting vital functions human cells. Defective interfering particles (DIPs) natural competitors viruses important resources DIPs emerge during infection, originate from normal replication process and inhibit its progression, making them an interesting candidate antiviral therapy. Here we describe biology DIPs, advances in DIP-based technology, analyze therapeutic potential provide a systemic overview existing preventive strategies.

Language: Английский

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Characterization of SARS-CoV-2 intrahost genetic evolution in vaccinated and non-vaccinated patients from the Kenyan population

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Abstract Vaccination is a key control measure of COVID-19 by preventing severe effects disease outcomes, reducing hospitalization rates and death, increasing immunity. However, vaccination can affect the evolution adaptation SARS-CoV-2, largely through vaccine-induced immune pressure. Here we investigated intrahost recombination single nucleotide variations (iSNVs) on SARS-CoV-2 genome in non-vaccinated vaccinated sequences from Kenyan population to profile viral genetic adaptations driven We identified hotspots S, N, ORF1a/b genes showed landscape comparing within-wave inter-wave events beginning pandemic (June 2020) (December 2022) Kenya. further reveal differential expression recombinant RNA species between individuals perform an in-depth analysis iSNVs identify characterize functional properties non-synonymous mutations found ORF-1 a/b, N genes. Lastly, detected minority variant patients Kenya, with escape mutation S255F spike gene species. Overall, this work unique vivo patterns which could have significant implications for virus evolution, virulence, escape.

Language: Английский

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Role of Defective Interfering Particles in Complement-Mediated Lysis of Parainfluenza Virus-Infected Cells

Viruses, Journal Year: 2025, Volume and Issue: 17(4), P. 488 - 488

Published: March 28, 2025

RNA viruses pose a significant global public health burden due to their high mutation rates, zoonotic potential, and ability evade immune responses. A common aspect of replication is the generation defective interfering particles (DIPs), which contain truncated viral genomes (DVGs) that depend on full-length standard (STD) virus for replication. DVGs have gained recognition as they are increasingly detected in clinical samples from natural infections. While role modulating type I interferon (IFN-I) responses well established, impact complement (C′) system not understood. In this study, we examined how influence C′-mediated lysis during parainfluenza 5 (PIV5) infection using real-time vitro cell viability assays. Our results demonstrated C′ effectively killed human lung epithelial cells infected with STD PIV5, whereas co-infection DIP-enriched stocks significantly suppressed killing through mechanisms were dependent DVG but independent IFN-I production. The titration DI units PIV5 showed strong linear relationship between DIP-mediated decreases surface glycoprotein expression inhibition lysis. findings reveal previously unrecognized function pathways, shedding light potential persistence evasion.

Language: Английский

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Validation of diverse and previously untraceable Sendai virus copyback viral genomes by Direct RNA Sequencing

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

Copyback viral genomes (cbVGs) are truncated with complementary ends produced when the negative-sense RNA virus polymerase detaches from replication template and resumes elongation nascent strand. Despite advances in methods to identify cbVGs based on site of break rejoin, PCR-based tools cannot provide full length sequences most and/or can introduce errors artifacts during cbVG amplification. These limitations have painted a limited picture diverse population generated infection. To improve our ability obtain native full-length cbVGs, we optimized Direct Sequencing (DRS) as fast simple tool sequence designed BLAST-based analysis approach long-read sequencing data. We analyzed DRS outputs multiple Sendai stocks highlight both utility this tool. found that capture dominant 546 nucleotide by strain Cantell, complementarity between trailer oligonucleotide should optimally be increased up 32 nucleotides. also demonstrate comparable quality little 17.6ng media fraction or 50ng cellular cells infected SeV, contrast recommended 1000ng. Importantly, validated different species two recombinant stocks, including for first time whose positions occurred at near position one reference genome. Most viruses order Mononegavirales has been demonstrated naturally generate copyback genomes. critical determinants infection outcomes; they interfere standard competing resources, activate antiviral responses, inhibit protein translation. their roles infection, current study rely either preexisting knowledge target require reverse-transcription amplification RNA, biasing toward short introducing relatively high rates errors. Our lab long advocated virologists assess role may infections. Toward effort, detail optimization while maintaining integrity present Long-Read Analysis (LoCA; https://github.com/lopezlab-washu/LOCA.git ) script highly accessible detection.

Language: Английский

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SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19

Cell Reports, Journal Year: 2025, Volume and Issue: 44(4), P. 115562 - 115562

Published: April 1, 2025

Aging-associated vulnerability to coronavirus disease 2019 (COVID-19) remains poorly understood. Here, we show that severe acute respiratory syndrome 2 (SARS-CoV-2)-infected aged mice lacking SIRT2, a cytosolic NAD+-dependent deacetylase, develop more and increased mortality, while treatment with an NAD+ booster, 78c, protects from lethal infection. Mechanistically, demonstrate SIRT2 modulates the acetylation of cyclic GMP-AMP synthase (cGAS), immune sensor for DNA, suppresses aging-associated cGAS activation inflammation. Furthermore, SARS-CoV-2 infection-induced inflammation is mediated at least in part by ORF3a, which triggers mtDNA release activation. Collectively, our study reveals molecular basis susceptibility COVID-19 suggests therapeutic approaches protect populations

Language: Английский

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Characterization of SARS-CoV-2 intrahost genetic evolution in vaccinated and non-vaccinated patients from the Kenyan population

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: May 6, 2025

ABSTRACT Vaccination is a key control measure of coronavirus disease 2019 by preventing severe effects outcomes, reducing hospitalization rates and death, increasing immunity. However, vaccination can affect the evolution adaptation SARS-CoV-2 largely through vaccine-induced immune pressure. Here, we investigated intrahost recombination single nucleotide variations (iSNVs) on acute respiratory syndrome 2 (SARS-CoV-2) genome in non-vaccinated vaccinated sequences from Kenyan population to profile viral genetic adaptations driven We identified hotspots S, N, ORF1a/b genes showed landscape comparing within- inter-wave events beginning pandemic (June 2020 December 2022) Kenya. further reveal differential expression recombinant RNA species between individuals perform an in-depth analysis iSNVs identify characterize functional properties non-synonymous mutations found ORF-1 a/b, N genes. Lastly, detected minority variant patients Kenya, with escape mutation S255F spike gene, species. Overall, this work unique vivo patterns SARS-CoV-2, which could have significant implications for virus evolution, virulence, escape. IMPORTANCE The impact diversity Kenya much Africa remains unknown. This be attributed lower sequencing rates; however, information relevant improvement vaccine antiviral research. In study, how transmission waves non-homologous (iSNVs). also demonstrate methodology studying changes pathogen simultaneous both events. study reveals highlights need sustained genomic surveillance better understand evolves. Such ensures detection drifts allowing updates vaccines, policy making, containment future variants SARS-CoV-2.

Language: Английский

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