Research Article: The TIR Homologue Lies near Resistance Genes in Staphylococcus aureus, Coupling Modulation of Virulence and Antimicrobial Susceptibility

Date Published: January 6, 2017

Publisher: Public Library of Science

Author(s): Sabine Patot, Paul RC Imbert, Jessica Baude, Patricia Martins Simões, Jean-Baptiste Campergue, Arthur Louche, Reindert Nijland, Michèle Bès, Anne Tristan, Frédéric Laurent, Adrien Fischer, Jacques Schrenzel, François Vandenesch, Suzana P Salcedo, Patrice François, Gérard Lina, Alice Prince.


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.

Partial Text

The innate immune system constitutes the first line of host defense against invading microbial pathogens in multicellular organisms. Key components of the innate immune response are pattern recognition receptors, which recognize a wide range of conserved bacterial structures, collectively called pathogen-associated molecular pattern and initiate an intracellular signaling immune cascade [1]. 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 TIR-containing 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 therefore plays a pivotal role in signaling from these receptors, and their importance in immune regulation has made them the subject of intense study.

Bacterial strategies for innate immune evasion involve manipulation of the TLR signaling by TIR homologues such as TirS for S. aureus [20]. In this work we report the localization of the tirS in different SCC elements and its role in the control of the inflammatory response during S. aureus infection. Using a mouse model of S. aureus skin infection, we evaluated the role of TirS on S. aureus virulence. We show that S. aureus Geraldine deleted for the tirS gene exhibited superior virulence compared to the WT strain, as attested by the size of the skin lesion. Of note, bacterial counts in the skin lesions did not differ between the mutant and the WT strains and did not correlate with clinical severity (i.e., lesion size). This finding suggests that bacterial burden may not be the primary driver of lesion severity and argues that lesion severity may be due, at least in part, to the associated inflammatory response. In support of this hypothesis, we found a correlation between lesion size and levels of the proinflammatory cytokines, as well as neutrophil activity (as assessed by MPO levels). These findings are consistent with previous studies, which underscores that the severity of skin infection is often driven by the inflammatory response to the invading pathogen as much or more than by the direct effects of the pathogen itself [21–23]. This inference suggests that the attenuation of skin inflammation observed with S. aureus WT strain, compared to its tirS mutant, was driven by modulation of the inflammation resulting from TirS action. Such a conclusion is concordant with the fact that the ectopic expression of TirS in eukaryotic cells appeared to temper stimuli-induced TLR2-, TLR4-, TLR5-, and TLR9-mediated NF-kB activation. Accordingly, a previous and independent work has reported a negative interference of TirS with the TLR2 signaling pathway [9]. These results can be directly linked to our in vivo observations in mice, explaining the modulation of virulence during S. aureus infection by tirS [4,20]. Here the bacterial TIR effector has been shown to induce attenuation of virulence during infection because of the downregulation of the innate immune pathway.




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