The synthetic food additive tert ‐butylhydroquinone impairs early NK cell responses to influenza

Abstract

Influenza virus is estimated to cause millions of illnesses and thousands of hospitalizations and deaths yearly in the United States, making influenza a major public health concern. It is well known that an early natural killer (NK) cell response against influenza is vital for effective viral clearance. Tert-butylhydroquinone (tBHQ) is a widely used food preservative with known immunomodulatory activity. Our lab has shown tBHQ to negatively impact NK cell activation, effector function, and maturation ex vivo. However, little is known regarding the effects of tBHQ consumption on NK cells in vivo, specifically in response to influenza infection. In the current study, we examined whether the consumption of tBHQ would impair NK cell response two and three days after primary influenza virus infection. Female C57Bl/6J mice were fed a diet containing either 0.0014% tBHQ or control diet 10 days prior to infection. Mice were intranasally infected with influenza A/PR/8/34 (H1N1), and at days two and three post-infection, lungs were collected and processed for analysis by flow cytometry, qPCR, and ELISA. Mice exhibited similar weight loss throughout infection regardless of their respective diet. There were no statistical differences in the infiltration or maturation of NK cells in the lungs between the groups at day two of infection. At day three, tBHQ modestly decreased the percentage of NK cells in the lung, and NK cells adopted a more immature phenotype. Notably, tBHQ significantly reduced expression of FasL and production of IFNγ in NK cells compared to those on a control diet at day two. NK cell cytotoxicity decreased with tBHQ at day three, as demonstrated by reduced CD107a expression. Likewise, induction of the effector genes was decreased in the lungs of mice on a tBHQ diet at days two and three of infection. Taken together, the data suggests the food additive, tBHQ, to negatively impact early NK cell responses to influenza infection by inhibiting FasL and CD107a expression and IFNγ production. Furthermore, tBHQ impaired the induction of genes associated with NK cell effector function in influenza-infected mice.