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bioRxiv · 10.1101/2023.05.30.542830

Staphylococcus aureus planktonic but not biofilm environment induces an IFN-β macrophage immune response via the STING/IRF3 pathway

Seebach, E.·Sonnenmoser, G.·Kubatzky, K. F.
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Abstract

Chronic implant-related bone infections are a severe complication in orthopedic surgery. Biofilm formation on the implant surface impairs an effective immune response leading to bacterial persistence. In a previous study, we found that Staphylococcus aureus (SA) induced IRF3 activation and Ifnb gene expression only in its planktonic form but not in the biofilm. The aim of this study was to clarify the role of the stimulator of interferon genes (STING) in this process. We treated murine RAW 264.7 macrophages with conditioned media (CM) generated from planktonic or biofilm cultured SA in combination with agonists or inhibitors of the cGAS/STING pathway. We further evaluated bacterial gene expression of planktonic and biofilm SA to find potential mediators. STING inhibition resulted in a loss of IRF3 activation and Ifnb induction in SA planktonic CM, whereas STING activation induced an IRF3 dependent IFN-{beta} response in SA biofilm CM. Expression levels of genes associated with virulence decreased with biofilm formation while those associated with cyclic dinucleotide (CDN) synthesis did not correlate with Ifnb induction. We further observed that cGAS contributed to the Ifnb induction by SA planktonic CM although cGAS activation was not sufficient to induce Ifnb gene expression in SA biofilm CM. Our data indicate that the different degrees of virulence associated with planktonic and biofilm SA environments result in an altered induction of an IRF3 mediated IFN-{beta} response via the STING pathway. This finding suggests that the STING/IRF3/IFN-{beta} axis is a potential candidate for further investigation as immunotherapeutic target in implant-related bone infections.

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Seebach, E., Sonnenmoser, G., Kubatzky, K. F.. 2023-05-30. Staphylococcus aureus planktonic but not biofilm environment induces an IFN-β macrophage immune response via the STING/IRF3 pathway. https://doi.org/10.1101/2023.05.30.542830

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