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2016 DEPARTMENT OF MEDICINE RESEARCH DAY Title of Poster: Staphylococcus aureus coopts cGAS-STING dependent type I interferon to subvert cutaneous host defense Presenter: Philip Scumpia Division: Dermatology ☒ Faculty ☐ Fellow ☐ Resident ☐ Post-doc Research Fellow ☐ Graduate Student ☐ Medical Student ☐Other Principal Investigator/Mentor: Stephen Smale Thematic Poster Category: Atherosclerosis Co-Investigators: Infections, Injury and Repair, Inflammation, Host Defense, Immunology, Hemostasis and Abstract Staphylococcus aureus is a commensal microorganism that resides on skin, but can cause severe skin and soft tissue infections once it invades epithelial surfaces. Understanding the initial interactions of S. aureus with innate immune cells may help identify immune pathways critical to host defense. To this end, we compared the early transcriptomic response of macrophages treated with live S. aureus (LSA) with those treated with heat-killed S. aureus (HKSA) to determine early immune pathways activated by infection. Using this approach, we identify the four major transcriptional programs activated early in macrophages by LSA. Two transcriptional programs induced by live bacteria: a type I interferon (IFN) antiviral response and a program important for initiating T cell differentiation required stimulator of interferon genes (STING) signaling for maximal induction. Activation of the STING programs requires live bacteria, and largely depends on activation of the DNA sensor cyclic guanosine-adenosine synthase (cGAS). Non-virulent S. epidermidis and virulent S. aureus strains also induce IFN- through STING, suggesting it as a common pathway triggered by Staphylococcal species. Cutaneous infection of STINGgt/gt mice with S. aureus results in impaired IFN- but higher levels of protective interleukin (IL)-1 and IL-12, enhanced neutrophil recruitment and activity, and improved clearance of S. aureus. Taken together, we identify early STING activation by S. aureus as a novel immune pathway exploited by S. aureus to suppress neutrophil dependent host defense.