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

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.