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.

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Résumé -Objectif : Le traitement de l'hypertension artérielle primaire fait appel à différents médicaments cardiotropes aux effets toxiques comparables. Notre travail relate, chez un patient traité pour hypertension, une double intoxication au vérapamil et au bisoprolol initialement étiquetée bisoprolol seul, lors d'un premier screening toxicologique large. Matériel et méthodes : Le diagnostic de cette intoxication a été obtenu par la répétition de recherches larges par une méthode CLHP/UV/BD. Résultats : La découverte de l'intoxication double au bisoprolol et au vérapamil a été permise grâce à deux screening toxicologiques successifs. Les concentrations toxiques de vérapamil sont apparues après la décroissance des concentrations toxiques de bisoprolol, expliquant la persistance, dans le temps, des symptômes cardiovasculaires. Cette intoxication a conduit le patient à séjourner en service de réanimation médicale pendant plusieurs jours. Les concentrations de vérapamil sont restées toxiques pendant 6 jours. Conclusion : Devant l'absence de modification des signes cliniques et la présence de forme galénique à libération prolongée, la répétition d'un screening toxicologique large plutôt qu'un dosage spécifique du toxique initialement suspecté, a permis le dépistage et le suivi d'une intoxication poly-médicamenteuse à molécules cardiotropes. Mots clés : Vérapamil, bisoprolol, intoxication, CLHPAbstract -Objective: Primary essential high blood pressure is treated by different cardiotropic drugs which have similar toxicological effects. Our study is about a verapamil and bisoprolol poisoning, which was at first labelled as bisoprolol only, after a comprehensive toxicological analysis. Materials and methods: This poisoning was diagnosed by repeated HPLC/UV/DAD screenings. Results: Two successive screenings showed both verapamil and bisoprolol poisoning. Verapamil toxic concentrations were revealed after the decrease in bisoprolol concentrations, explaining the persistence in time of cardiovascular symptoms. The patient stayed for several days in an intensive care unit. Verapamil concentrations remained at a toxic level for six days. Conclusion: Because of the presence of sustained-release forms and unchanged clinical signs, repeating a comprehensive toxicological screening, instead of monitoring the initially suspected drug, helped in the screening and the follow-up of this multiple cardiotopic drug poisoning.