Heterogeneity of Host TLR2 Stimulation by Staphylocoocus aureus Isolates

Abstract

High lipoprotein expression and potent activation of host Toll-like receptor-2 (TLR2) are characteristic features of the staphylococcal species. Expression of TLR2 in the host is important for clearance of Staphylococcus aureus infection and host survival. Thus, we hypothesized that bacterial regulation of its intrinsic TLR2-stimulatory capacity could represent a means for immune evasion or host adaptation. We, therefore, compared clinical S. aureus isolates in regards to their TLR2 activation potential and assessed the bacterial factors that modulate TLR2-mediated recognition. S. aureus isolates displayed considerable variability in TLR2-activity with low to absent TLR2-activity in 64% of the isolates tested (68/106). Notably, strain-specific TLR2-activity was independent of the strain origin, e.g. no differences were found between strains isolated from respiratory specimen from cystic fibrosis patients or those isolated from invasive disease specimen. TLR2-activity correlated with protein A expression but not with the agr status. Capsule expression and small colony variant formation had a negative impact on TLR2-activity but any disruption of cell wall integrity enhanced TLR2 activation. Altogether, heterogeneity in host TLR2-activity reflects differences in metabolic activity and cell wall synthesis and/or remodeling.

Inflammatory properties of antibiotic-treated bacteria

“…Typically, antibiotics that inhibit protein synthesis cause less release of bacterial products as they kill. For example, whereas treatment of S. aureus with the cell wall activate antibiotic vancomycin enhances its ability to stimulate cytokine production by macrophages and via TLR2, exposure to the protein synthesis inhibitor antibiotic linezolid suppresses these responses [10,11].The exact reason for this observation is not completely clear. It could be decreased PAMP synthesis or the lack of bacterial lysis.…”

Contribution of the Immune Response to Phage Therapy

“…Notably, an important principle of treatment with bacteriostatic antibiotics is that antibiotic control of bacterial proliferation and spread enables bacterial clearance by host immune cells. Furthermore, antibiotic-mediated damage of bacterial cells facilitates phagosomal lysis and release of pathogen-associated molecular patterns (PAMPs), which enhance bacterial clearance by activating the innate immune system (3)(4)(5)(6). In cases of high bacterial burden, excess release of high amounts of endotoxin (i.e., LPS and other PAMPs) following administration of the antibiotic promotes a systemic inflammatory reaction that can require medical intervention (7).…”

Uncoupling of Pro- and Anti-Inflammatory Properties of Staphylococcus aureus

“…If so, the relative abundance of the pro-versus anti-inflammatory ligands would dictate the outcome of the response. We cannot rule out that under some circumstances (e.g., S. aureus isolates lacking TLR2-stimulatory capacity [43]) an IL-10 response may occur through an alternative, less efficient mechanism.…”