Journal Article

NRF2 Antioxidant Response and Interferon‐Stimulated Genes Are Differentially Expressed in SARS‐CoV‐2‐Positive Young Subjects

Anna Teresa, Palamara, Maria Elena, Marcocci, Raffaella, Nenna, Marta, De Angelis, Fabio, Midulla, Elena, Piselli, Guido, Antonelli, Matteo, Fracella, Leonardo, Sorrentino, Walter, Toscanelli, Alessandra, Pierangeli, Enrica, Mancino, Lucia, Nencioni, Laura, Petrarca, Carolina, Scagnolari

2025

Overview

ABSTRACT Background Several respiratory viruses, including Severe Acute Respiratory Syndrome‐Coronavirus‐2 (SARS‐CoV‐2), suppress nuclear factor‐E2‐related factor‐2 (NRF2) antioxidant response, generating oxidative stress conditions to its advantage. NRF2 has also been reported to regulate the innate immune response through the inhibition of the interferon (IFN) pathway. However, its modulation in younger individuals and its correlation with the IFN response remain to be elucidated. Methods The NRF2 and redox‐related genes expression was examined in nasopharyngeal swabs from children attending the pediatric hospital for SARS‐CoV‐2 molecular testing. Expression levels were analyzed by stratifying the population according to the SARS‐CoV‐2 positivity, age, or the presence of symptoms. The results were correlated with Types I and III IFN genes and IFN‐stimulated genes (ISGs). Results We found that NRF2 expression was markedly diminished in positive patients compared to negative. Moreover, it correlated with higher expression of IFNα2 and IFNλ3, as well as ISG15 and ISG56. Interestingly, symptomatic patients with anosmia/ageusia showed pronounced expression of apurinic/apyrimidinic endonuclease1/redox factor 1 (APE1), together with Type I IFNs, ISG56, and the inflammasome component NLRP3. Conclusion The results indicate an interdependence between NRF2 antioxidant pathway and IFN‐mediated response during SARS‐CoV‐2 infection in young subjects. This study highlights the role of NRF2 and related genes in the regulation of the IFN response in SARS‐CoV‐2‐positive children. We confirmed that SARS‐CoV‐2 infection inhibits the NRF2‐mediated antioxidant response in the upper respiratory tract also in pediatric subjects, although NRF2 was less expressed in asymptomatic subjects compared to groups with mild symptoms, in which inflammatory genes were upregulated. The observed suppression of NRF2 and its correlation with high increases of IFNα2 and IFNλ3 response, along with increased expression of ISGs, provide valuable insights into the host response to the virus in the young population. Further investigations are warranted to explore the potential of NRF2 modulators as therapeutic strategies for COVID‐19, particularly, in children.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Adolescent / antioxidant response / Antioxidants / Antioxidants - metabolism / APE‐1 / Asymptomatic / Child / Child, Preschool / COVID-19 / COVID-19 - genetics / COVID-19 - immunology / COVID-19 - metabolism / COVID-19 - virology / Cytokines - genetics / Disease transmission / Enzymes / Female / Gene expression / Gene Expression Regulation / Humans / Immunity, Innate / Infant / Infections / inflammasome / Influenza / Interferon Lambda / Interferon response / Interferons - genetics / Interferons - metabolism / Interleukins / Male / NF-E2-Related Factor 2 - genetics / NF-E2-Related Factor 2 - metabolism / NRF2 / Olfaction disorders / Original / Oxidative Stress / Pediatrics / Physiology / Proteins / SARS-CoV-2 - immunology / SARS‐CoV‐2 / Severe acute respiratory syndrome coronavirus 2 / Statistical analysis / Taste disorders / Teenagers / Ubiquitins / Viral infections / Viruses