The Influence of Flavonoid Compositions on Nrf2 Transcription Factor Expression in Case of Infections Triggered by Influenza A Virus and Transmissible Gastroenteritis Coronavirus

Abstract

Background. Viral infections trigger transcription factors, including Nrf2, which regulate the expression of genes related to cytokines, chemokines, and more. Nuclear factor erythroid 2-related factor 2 (Nrf2) participates in complex regulatory networks controlling the expression of cytoprotective genes and immune responses. Recently, new roles have been attributed to Nrf2, including the regulation of antiviral responses. Objective. The aim of the study was to analyze Nrf2 activation in influenza virus infection in vivo and in transmissible gastroenteritis coronavirus (TGEV) infection in vitro, as well as the effects of the flavonoid compositions Proteflazidum® and Protoil on the Nrf2 expression in these two experimental models of viral infection. Methods. Outbred white mice were infected with influenza A virus (A/FM/1/47/H1N1 strain). Jurkat cells were infected with TGEV, previously adapted to these cells. Flavonoid compositions Proteflazidum® and Protoil (Ecopharm, Ukraine), containing the mixture of tricin, luteolin, apigenin, quercetin, and rhamnosin, were used in corresponding dilutions. Real-Time PCR was employed to analyze Nrf2 RNA expression in the lungs of mice and in both uninfected and virus-infected cells. Additionally, ELISA was used to assess the expression of Nrf2 peptide. Results. The Nrf2 expression in the lungs of influenza virus-infected mice showed a tendency to increase within a 100-fold range. In virus-infected mice treated with Proteflazidum® or Protoil, the level of Nrf2 expression in the lungs decreased about 10-fold compared to infected untreated mice. TGEV infection resulted in 100-fold increase in Nrf2 expression in Jurkat cells. Both Proteflazidum® and Protoil decreased Nrf2 expression in TGEV-infected cells, while their effects on Nrf2 expression in the intact cells on Day 1 were not detected. Conclusions. Flavonoid compositions have only a slight effect on Nrf2 expression in intact cells. However, in case of virus infection, both in vivo and in vitro, they counteract the extensive up-regulation of Nrf2 expression due to viral infection.