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Toll/interleukin-1 receptor (TIR) domains in Toll-like receptors are essential for initiating and propagating the eukaryotic innate immune signaling cascade. Here, we investigate TirS, a Staphylococcus aureus TIR mimic that is part of a novel bacterial invasion mechanism. Its ectopic expression in eukaryotic cells inhibited TLR signaling, downregulating the NF-kB pathway through inhibition of TLR2, TLR4, TLR5, and TLR9. Skin lesions induced by the S. aureus knockout tirS mutant increased in a mouse model compared with wild-type and restored strains even though the tirS-mutant and wild-type strains did not differ in bacterial load. TirS also was associated with lower neutrophil and macrophage activity, confirming a central role in virulence attenuation through local inflammatory responses. TirS invariably localizes within the staphylococcal chromosomal cassettes (SCC) containing the fusC gene for fusidic acid resistance but not always carrying the mecA gene. Of note, sub-inhibitory concentration of fusidic acid increased tirS expression. Epidemiological studies identified no link between this effector and clinical presentation but showed a selective advantage with a SCCmec element with SCC fusC/tirS. Thus, two key traits determining the success and spread of bacterial infections are linked., Author Summary Pathogenic microbes have evolved elaborate strategies to manipulate host defenses to establish and spread in the host population. One such mechanism involves disruption of the immune signaling cascade orchestrated by the Toll-like receptors (TLRs), which sense microbial attack. TLR signaling elicits a proinflammatory response that controls immune cell recruitment to infected tissues. Here, we show that Staphylococcus aureus, an opportunistic human pathogen, expresses a host defense–like protein, TirS, that actively perturbs the initial TLR activation stage. Results with isolated human cells and mouse models show that TirS is a broad innate immune inhibitor of TLR-dependent signaling and modulates bacterial virulence, attenuating local inflammation. Moreover, the tirS gene lies near antimicrobial resistance genes for an antibiotic that enhances TirS production, shifting the balance to favor the pathogen and promote disease. Understanding mechanisms by which S. aureus modulates the immune response may lead to novel approaches for preventing and treating infection.