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Successful host defense against pathogens requires innate immune recognition of the correct pathogen associated molecular patterns (PAMPs) by pathogen recognition receptors (PRRs) to trigger the appropriate gene program tailored to the pathogen. While many PRR pathways contribute to the innate immune response to specific pathogens, the relative importance of each pathway for the complete transcriptional program elicited has not been examined in detail. Herein, we used RNA-sequencing with wildtype and mutant macrophages to delineate the innate immune pathways contributing to the early transcriptional response to  Staphylococcus aureus , a ubiquitous microorganism that can activate a wide variety of PRRs. Unexpectedly, two PRR pathways—the Toll-like receptor (TLR) and Stimulator of Interferon Gene (STING) pathways—were identified as dominant regulators of approximately 95% of the genes that were potently induced within the first four hours of macrophage infection with live  S .  aureus . TLR signaling predominantly activated a pro-inflammatory program while STING signaling activated an antiviral/type I interferon response with live but not killed  S .  aureus . This STING response was largely dependent on the cytosolic DNA sensor cyclic guanosine-adenosine synthase (cGAS). Using a cutaneous infection model, we found that the TLR and STING pathways played opposite roles in host defense to  S .  aureus . TLR signaling was required for host defense, with its absence reducing interleukin (IL)-1β production and neutrophil recruitment, resulting in increased bacterial growth. In contrast, absence of STING signaling had the opposite effect, enhancing the ability to restrict the infection. These results provide novel insights into the complex interplay of innate immune signaling pathways triggered by  S .  aureus  and uncover opposing roles of TLR and STING in cutaneous host defense to  S .  aureus .

Opposing roles of Toll-like receptor and cytosolic DNA-STING signaling pathways for Staphylococcus aureus cutaneous host defense