E of S. suis, several in vitro studies with ST1 strains have previously shown that TLR2 plays an important role during bacterial interactions with mouse, swine and human cells [18?0,30]. In addition, in vitro data suggest that activation pattern of TLR of typical ST1 European strains and that responsible for the Chinese human outbreak of toxic shocklike syndrome may slightly differ [20]. However, the in vivo contribution of TLR2 to the pathology of S. suis acute systemic infections has so far never been studied. Our data indicate that in vivo TLR2-mediated recognition significantly contributes to the severe outcome following infection with a highly virulent S. suis ST1 strain. The absence of mortality could not be associated with a lower bacterial burden, suggesting that TLR2 would not be directly implicated in bacterial killing. In fact, recent results showed that dendritic cells from myeloid differentiation factor 88 deficient mice (MyD882/2) presented similar rates of phagocytosis and killing of S. suis serotype 2 than cells isolated from WT mice [31], suggesting that TLRs would probably not be implicated in S. suis clearance. On the other hand, microarray, qRT-PCR, and/or protein assays confirmed a significantly lower induction of proinflammatory cytokines and chemokines in TLR22/2 mice that would correlate with survival, confirming previous in vitro results [18,19]. Previous studies showed that the susceptibility of animals after experimental infection with S. suis serotype 2 clearly correlated with levels of inflammatory mediators in plasma 18204824 K162 site rather than bacteremia [23]. Levels of proteins in plasma were similar to those obtained from homogenized spleen from infected mice (unpublished observations). In vivo results obtained with S. suis are similar to those reported by Mancuso et al. with Group B Streptococcus (GBS) who showed that,at high bacterial concentrations, TLR22/2 mice presented similar levels of bacteremia but considerably lower levels of inflammatory mediators and less mortality than WT mice [17]. However, and differently from S. suis, TLR2 plays an important role in controlling GBS infection when mice are infected with low doses of bacteria [17]. Infections with lower S. suis concentrations (#56106 CFU/mL) did not BIBS39 web induce clinical disease in any of the mouse 23148522 strains tested (results not shown). It is important to note that the pathogenesis of S. suis and GBS differ mainly in that the capsular polysaccharide of these pathogens present high or low anti-phagocytic properties, respectively [32]. Interestingly, inflammatory mediators were significantly reduced but not abolished in TLR22/2 infected mice, suggesting the contribution of other receptors. In vitro studies with S. suis ST1 strains recently showed that TLRs other than TLR2 as well as nonTLR receptors, such as nucleotide-binding oligomerization domain-like receptor (NLR) families, TLR3, TLR6 and TLR9 may also be involved in cell activation [31]. In fact, mice infected with very high doses of both S. suis ST1 and ST7 ( 16108 CFU/mL) died within 72 h of infection indicating that although TLR2 seems to play an important role, in vivo activation of host cells by S. suis would require a multimodal recognition system (results not shown). Serious outbreaks of S. suis STSLS in humans caused by an atypical strain have been reported during the last few years in China [33]. The ST7 strain was already shown to possess both higher inflammatory and virulence capacities than those o.E of S. suis, several in vitro studies with ST1 strains have previously shown that TLR2 plays an important role during bacterial interactions with mouse, swine and human cells [18?0,30]. In addition, in vitro data suggest that activation pattern of TLR of typical ST1 European strains and that responsible for the Chinese human outbreak of toxic shocklike syndrome may slightly differ [20]. However, the in vivo contribution of TLR2 to the pathology of S. suis acute systemic infections has so far never been studied. Our data indicate that in vivo TLR2-mediated recognition significantly contributes to the severe outcome following infection with a highly virulent S. suis ST1 strain. The absence of mortality could not be associated with a lower bacterial burden, suggesting that TLR2 would not be directly implicated in bacterial killing. In fact, recent results showed that dendritic cells from myeloid differentiation factor 88 deficient mice (MyD882/2) presented similar rates of phagocytosis and killing of S. suis serotype 2 than cells isolated from WT mice [31], suggesting that TLRs would probably not be implicated in S. suis clearance. On the other hand, microarray, qRT-PCR, and/or protein assays confirmed a significantly lower induction of proinflammatory cytokines and chemokines in TLR22/2 mice that would correlate with survival, confirming previous in vitro results [18,19]. Previous studies showed that the susceptibility of animals after experimental infection with S. suis serotype 2 clearly correlated with levels of inflammatory mediators in plasma 18204824 rather than bacteremia [23]. Levels of proteins in plasma were similar to those obtained from homogenized spleen from infected mice (unpublished observations). In vivo results obtained with S. suis are similar to those reported by Mancuso et al. with Group B Streptococcus (GBS) who showed that,at high bacterial concentrations, TLR22/2 mice presented similar levels of bacteremia but considerably lower levels of inflammatory mediators and less mortality than WT mice [17]. However, and differently from S. suis, TLR2 plays an important role in controlling GBS infection when mice are infected with low doses of bacteria [17]. Infections with lower S. suis concentrations (#56106 CFU/mL) did not induce clinical disease in any of the mouse 23148522 strains tested (results not shown). It is important to note that the pathogenesis of S. suis and GBS differ mainly in that the capsular polysaccharide of these pathogens present high or low anti-phagocytic properties, respectively [32]. Interestingly, inflammatory mediators were significantly reduced but not abolished in TLR22/2 infected mice, suggesting the contribution of other receptors. In vitro studies with S. suis ST1 strains recently showed that TLRs other than TLR2 as well as nonTLR receptors, such as nucleotide-binding oligomerization domain-like receptor (NLR) families, TLR3, TLR6 and TLR9 may also be involved in cell activation [31]. In fact, mice infected with very high doses of both S. suis ST1 and ST7 ( 16108 CFU/mL) died within 72 h of infection indicating that although TLR2 seems to play an important role, in vivo activation of host cells by S. suis would require a multimodal recognition system (results not shown). Serious outbreaks of S. suis STSLS in humans caused by an atypical strain have been reported during the last few years in China [33]. The ST7 strain was already shown to possess both higher inflammatory and virulence capacities than those o.
