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8-Oxoguanine DNA glycosylase 1 hijacked by nucleoprotein conceals guanine oxidation in respiratory syncytial virus RNA

ABSTRACT: Respiratory Syncytial Virus (RSV), alongside other prominent respiratory RNA viruses such as influenza and SARS-CoV-2, significantly contributes to the global incidence of respiratory tract infections. These pathogens prompt the production of reactive oxygen species (ROS), which play a crucial role in the onset and progression of respiratory diseases. However, the strategies by which viral RNA manages ROS-induced base oxidation are not well understood. Here we uncover that 8-oxo-7,8-dihydroguanine (8-oxoGua) is not merely an incidental byproduct of ROS activity but serves as a strategic adaptation of RSV RNA during replication within host cells. Through RNA immunoprecipitation and next-generation sequencing, we discovered that 8-oxoguanine DNA glycosylase 1 (OGG1) binding sites are predominantly found in the RSV antigenome, especially within guanine-rich areas. Further investigation revealed that viral ribonucleoprotein complexes specifically hijack OGG1. Crucially, our findings show that inhibiting OGG1's ability to recognize 8-oxoGua leads to a substantial reduction in RSV progeny production. Our results underscore the viral replication machinery's adaptation to oxidative challenges, pointing to the inhibition of OGG1's reading function as a potential novel strategy for antiviral intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269769 | GEO | 2024/06/13

REPOSITORIES: GEO

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8-Oxoguanine DNA glycosylase 1 conceals guanine oxidation in nucleoprotein-associated RNA of respiratory syncytial virus

Project description:Respiratory syncytial virus (RSV), along with other prominent respiratory RNA viruses such as influenza and SARS-CoV-2, significantly contributes to the global incidence of respiratory tract infections. These pathogens induce the production of reactive oxygen species (ROS), which play a crucial role in the onset and progression of respiratory diseases. However, the mechanisms by which viral RNA manages ROS-induced base oxidation remain poorly understood. Here we reveal that 8-oxo-7,8-dihydroguanine (8-oxoGua) is not merely an incidental byproduct of ROS activity but serves as a strategic adaptation of RSV RNA to maintain genetic fidelity within host cells. Through 8-oxoguanine DNA glycosylase 1 (OGG1) immunoprecipitation and LC_MS/MS, we discovered that RSV nucleoprotein is a principal partner of OGG1. Further investigation revealed that viral ribonucleoprotein complexes specifically hijack OGG1. Importantly, inhibiting OGG1's ability to recognize 8-oxoGua significantly reduces RSV progeny production. Our results underscore the viral replication machinery's adaptation to oxidative challenges, suggesting that inhibiting OGG1's reading function could be a novel strategy for antiviral intervention.

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8-Oxoguanine DNA glycosylase 1 hijacked by nucleoprotein conceals guanine oxidation in respiratory syncytial virus RNA

Project description:8-Oxoguanine DNA glycosylase 1 hijacked by nucleoprotein conceals guanine oxidation in respiratory syncytial virus RNA

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Project description:Background: There is limited data on how different RSV genotypes and associated viral loads influence disease phenotypes. We characterized the genetic variability of RSV strains during five non-consecutive respiratory seasons, and evaluated the role of RSV subtypes, genotypes and viral loads on clinical disease severity. Methods: Healthy infants hospitalized with RSV bronchiolitis were prospectively enrolled and nasopharyngeal samples obtained within 24h of hospitalization for RSV load quantitation by PCR, typing and genotyping. Parameters of disease severity were assessed, and multivariate models constructed to identify virologic and clinical factors predictive of clinical outcomes. Results: From March 2004 to April 2011, we enrolled 253 patients (56.5 % males; median age 2.1 (1.1-4.0) months). RSV A infections predominated over RSV B (69% vs. 31%; p<0.001) and showed greater genotype variability. The most common genotypes were RSV A/GA2, A/GA5 and RSV B/BA. Infants infected with RSV GA5 had higher viral loads compared with GA2 or BA infection (p<0.01), independent of duration of symptoms. After adjusting for other covariates, RSV A/GA5 infections were associated with longer hospital stay. Conclusions: RSV A infections were more frequent than RSV B infections and displayed greater genetic variability. Infections with GA5 were independently associated with clinical disease severity.

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