The TLR2 Antagonist Staphylococcal Superantigen-Like Protein 3 Acts as a Virulence Factor to Promote Bacterial Pathogenicity in vivo

Abstract

Toll-like receptor (TLR) signaling is important in the initiation of immune responses and subsequent instigation of adaptive immunity. TLR2 recognizes bacterial lipoproteins and plays a central role in the host defense against bacterial infections, including those caused by Staphylococcus aureus. Many studies have demonstrated the importance of TLR2 in murine S. aureus infection. S. aureus evades TLR2 activation by secreting two proteins, staphylococcal superantigen-like protein 3 (SSL3) and 4 (SSL4). In this study, we demonstrate that antibodies against SSL3 and SSL4 are found in healthy individuals, indicating that humans are exposed to these proteins during S. aureus colonization or infection. To investigate the TLR2-antagonistic properties of SSL3 and SSL4, we compared the infection with wild-type and SSL3/4 knockout S. aureus strains in an intravenous murine infection model. Direct evaluation of the contribution of SSL3/4 to infection pathogenesis was hindered by the fact that the SSLs were not expressed in the murine system. To circumvent this limitation, an SSL3-overproducing strain (pLukM-SSL3) was generated, resulting in constitutive expression of SSL3. pLukM-SSL3 exhibited increased virulence compared to the parental strain in a murine model that was found to be TLR2 dependent. Altogether, these data indicate that SSL3 contributes to S. aureus virulence in vivo.

Activation of a Bovine Mammary Epithelial Cell Line by Ruminant-Associated Staphylococcus aureus is Lineage Dependent

“…Expression levels of CP and WTA in S. aureus is highly variable and are tightly controlled by multiple systems, including repressor of toxins (rot) and the accessory gene regulator (agr) system, which is divided into four separate groups (I-IV) based on polymorphisms of agr genes [37]. In addition, these regulatory systems also control expression and release of PAMPs, such as PSMs [38], and immune evasion factors that inhibit TLR-2 activation [12]. Since the CCs tested in this study belong to different agr types (CC133 to agr type I and CC151, CC479, CC425 to type II) [16,39] and CC479 S. aureus have been reported to carry a non-functional copy of the rot gene [23], differences in expression of these agr/rot controlled genes are likely and could be a possible explanation for the differential bMEC response towards ruminant-associated CCs.…”

“…This might be explained by the large number of immune evasion molecules produced by S. aureus, several of which affect host recognition of the bacteria [11]. For instance, the exo-protein Staphylococcal superantigen-like protein (SSL) 3 binds to the extracellular part of TLR-2 without activating the cell [12]. Moreover, S. aureus reduces contact between PAMPs and host PRRs by covering its surface with capsular polysaccharides (CPs) [13] and wall teichoic acids (WTAs) [14].…”

“…Moreover, S. aureus reduces contact between PAMPs and host PRRs by covering its surface with capsular polysaccharides (CPs) [13] and wall teichoic acids (WTAs) [14]. Experimental overexpression or deletion of these immune evasion factors affects the virulence of S. aureus [12,14].…”

<b><i>Journal of Innate Immunity</i></b> Ten Years Later

“…It is, by some measures, the most important type of immunity we have.” has lost none of its actuality. From the beginning, the journal has been covering research in the area of innate immunity in a broad sense, for example invertebrate immunity [4-6], innate recognition [7-9], the cell biology of innate immune cells [10-12], and complex human diseases [13-15]. …”

Bystander Cells Taking Action

“…The key importance of and continued research interest in Toll-like receptors are reflected in the articles by Yan et al [16] and Koymans et al [17]. Despite the fact that the discovery of their importance in innate immunity was more than 2 decades ago, they continue to surprise with regard to their broad effects on regulating both innate and adaptive immunity [18,19,20,21].…”