The Immune Response to Influenza is Suppressed by the Synthetic Food Additive and Nrf2 Activator, tert‐butylhydroquinone (tBHQ)
Authors: Freeborn Robert A , Boss Allison P , Liu Sheng , Jin Yining , Brocke Stephanie , Turley Alexandra E , Zagorski Joseph W , Kennedy Rebekah C , Gardner Elizabeth M , Rockwell Cheryl E 
Published: June 2021

Influenza virus infections have been a persistent threat to society, causing up to 650,000 respiratory deaths annually world‐wide. The United States alone suffered 80,000 influenza‐related deaths during the 2017/18 flu season. Although vaccine coverage has increased in the U.S., this has not correlated with a decline in influenza‐related infections or deaths. Accordingly, there is significant interest in the identification of environmental factors which may contribute to influenza burden and/or reduce vaccine efficacy. Previous work from our laboratory demonstrated that a widely‐used food additive, ‐tert‐butylhydroquinone (tBHQ), impairs human CD4+ T cell activation and murine TH1 cell polarization (important in anti‐viral defense) ex vivo. These effects occurred through activation of the stress‐activated transcription factor, nuclear factor erythroid 2‐related factor 2 (Nrf2), as evidenced using Nrf2‐deficient human and murine models. Under basal conditions, Nrf2 is repressed in the cytosol by its repressor protein, Kelch‐like ECH‐associated protein 1 (Keap1), where it is quickly degraded via the 26S proteasome pathway. Upon the introduction of cell stress, such as the electrophilic stress induced by tBHQ, the interactions between Nrf2 and Keap1 are disrupted such that Nrf2 is no longer degraded, and Nrf2 accumulates in the nucleus where it upregulates cytoprotective genes. Studies from our lab and others have demonstrated immunomodulatory roles for Nrf2, including effects on macrophages, dendritic cells, and T cells. The tBHQ‐mediated decrease in Th1 polarization led us to hypothesize that consumption of the Nrf2 activator, tBHQ, would impair the T cell‐mediated immune response to acute influenza infection. To test this hypothesis, mice on either a low‐dose tBHQ or control diet were infected with influenza A/PR/8/34 (H1N1). tBHQ exposure impaired CD8+ T cell infiltration in the lung, CD4+/CD8+ T cell activation and effector function, the numbers of influenza‐specific T cells in the draining lymph nodes, and viral clearance. Interestingly, although we did not observe a decrease in the number of TH1 cells with tBHQ exposure at this timepoint (10 days post‐infection), there was an increase in the expression of the immunosuppressive proteins, CTLA‐4 and IL‐10. Of importance, the impaired immune response during primary infection correlated with more severe weight loss and prolonged infection during subsequent infection with a related strain of influenza (x31), indicating that tBHQ impaired the heterosubtypic memory response. Notably, an impaired heterosubtypic memory response would be expected to reduce vaccine efficacy. Overall, this study shows that tBHQ, at a dose relevant to human diet, impairs the primary and memory immune responses to influenza infection.Support or Funding InformationThis work was supported by NIH grants ES024966 and GM092715.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.