# STING contributes to the inflammation and proliferation of Staphylococcus aureus via mitochondrial reactive oxygen species–hypoxic inducible factor 1α axis in epithelial cells

## TL;DR

This study shows that the STING pathway promotes inflammation and bacterial growth during Staphylococcus aureus infection by activating a mitochondrial ROS-HIF1α-glycolysis pathway in epithelial cells.

## Contribution

The study reveals a novel role of STING in bacterial infection through the mROS-HIF1α-glycolysis axis.

## Key findings

- STING activation increases inflammation, HIF1α, and mROS during S. aureus infection.
- Blocking STING or HIF1α reduces inflammation and bacterial proliferation.
- STING-driven inflammation is linked to HIF1α-mediated glycolysis.

## Abstract

Staphylococcus aureus infection poses a serious threat to the dairy industry and public health safety. The stimulator of interferon gene (STING) signaling pathway has been well established as effective in defending against viral infections. However, the role of STING is controversial during bacterial infections. Herein, we provide an insight into the role of STING during S. aureus infection. Our data revealed that the STING signaling pathway was activated in S. aureus-infected cells. In vitro investigations demonstrated that inhibiting STING reduced inflammation, hypoxia-inducible factor-1 alpha (HIF1α) expression, and mitochondrial reactive oxygen species (mROS) production. Interestingly, blocking HIF1α eliminated the escalation of inflammation associated with STING. Additionally, suppressing mROS production significantly reduced HIF1α expression and inflammation levels, while elevating mROS had the opposite effect. These results indicate that STING promoted inflammation through the mROS-HIF1α pathway. Given that glycolysis is driven by HIF1α, we investigated the role of glycolysis during infection. As expected, STING-elevated inflammation was linked with HIF1α-driven glycolysis. In terms of pathogenesis, STING contributed to S. aureus proliferation within cells and mouse mammary glands. Collectively, our findings demonstrate that STING facilitates infection via the mROS-HIF1α-glycolysis axis, highlighting its potential as a promising anti-inflammatory target.