The TIR Homologue Lies near Resistance Genes in Staphylococcus aureus, Coupling Modulation of Virulence and Antimicrobial Susceptibility.
Sabine PatotPaul ImbertJessica BaudePatricia Martins SimõesJean-Baptiste CampergueArthur LoucheReindert NijlandMichèle BèsAnne TristanFrédéric LaurentAdrien FischerJacques SchrenzelFrançois VandeneschSuzana P SalcedoPatrice FrançoisGérard LinaPublished in: PLoS pathogens (2017)
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.
Keyphrases
- wild type
- staphylococcus aureus
- toll like receptor
- inflammatory response
- escherichia coli
- immune response
- biofilm formation
- genome wide
- nuclear factor
- poor prognosis
- mouse model
- copy number
- pseudomonas aeruginosa
- innate immune
- methicillin resistant staphylococcus aureus
- genome wide identification
- induced apoptosis
- antimicrobial resistance
- signaling pathway
- cystic fibrosis
- oxidative stress
- long non coding rna
- regulatory t cells
- transcription factor
- dendritic cells
- gene expression
- cell proliferation