Abstract
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.
Highlights
The innate immune system constitutes the first line of host defense against invading microbial pathogens in multicellular organisms
Among the 226 strains examined, 28 (12.4%) yielded positive tirS amplification (Table 1). tirS was detected in MRSA and MSSA strains belonging to only 3 clonal complexes (CCs): CC1, CC5, and CC8
We examined the molecular epidemiology of tirS in human staphylococcal infections
Summary
The innate immune system constitutes the first line of host defense against invading microbial pathogens in multicellular organisms. The Toll-like receptor/interleukin (IL)-1 receptor (TLR/IL-1R) superfamily, which comprises Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs), is required for many host innate immune responses and characterized by the presence of Toll/ interleukin-1 receptor (TIR) domains cytoplasmically located on each TLR [2]. The TIR domain is critical for protein–protein interactions between TLRs with the corresponding TIRcontaining adaptors. These interactions activate specific transcription factors such as nuclear factor-κB (NF-κB), which regulates the expression of various inflammatory mediators [3,4]. The TIR domain plays a pivotal role in signaling from these receptors, and their importance in immune regulation has made them the subject of intense study
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