Our study highlights the roles of surfactant-like molecules in bacterial inflammation with important implications for the prevention and therapy of inflammatory disorders. It describes a potential pathway for the transfer of hydrophobic bacterial lipoproteins, the major TLR2 agonists, from the cytoplasmic membrane of Gram-positive bacteria to the TLR2 receptor at the surface of host cells. Moreover, our study reveals a molecular mechanism that explains how cytoplasmic and membrane-embedded bacterial proteins can be released by bacterial cells without using any of the typical protein secretion routes, thereby contributing to our understanding of the processes used by bacteria to communicate with host organisms and the environment.
Sepsis caused by Gram-positive bacterial pathogens is a major fatal disease but its molecular basis remains elusive. Toll-like receptor 2 (TLR2) has been implicated in the orchestration of inflammation and sepsis but its role appears to vary for different pathogen species and clones. Accordingly, Staphylococcus aureus clinical isolates differ substantially in their capacity to activate TLR2. Here we show that strong TLR2 stimulation depends on high-level production of phenol-soluble modulin (PSM) peptides in response to the global virulence activator Agr. PSMs are required for mobilizing lipoproteins, the TLR2 agonists, from the staphylococcal cytoplasmic membrane. Notably, the course of sepsis caused by PSM-deficient S. aureus is similar in wild-type and TLR2-deficient mice, but TLR2 is required for protection of mice against PSM-producing S. aureus. Thus, a crucial role of TLR2 depends on agonist release by bacterial surfactants. Modulation of this process may lead to new therapeutic strategies against Gram-positive infections.
Antimicrobial fatty acids (AFAs) protect the human epidermis against invasion by pathogenic bacteria. In this study, we questioned whether human skin fatty acids (FAs) can be incorporated into the lipid moiety of lipoproteins and whether such incorporation would have an impact on innate immune stimulation in the model organism Staphylococcus aureus USA300 JE2. This organism synthesized only saturated FAs. However, when feeding USA300 with unsaturated FAs present on human skin (C 16:1 , C 18:1 , or C 18:2 ), those were taken up, elongated stepwise by two carbon units, and finally found in the bacterial (phospho)lipid fraction. They were also observed in the lipid moiety of lipoproteins. When USA300 JE2 was fed with the unsaturated FAs, the cells and cell lysates showed an increased innate immune activation with various immune cells and peripheral blood mononuclear cells (PBMCs). Immune activation was highest with linoleic acid (C 18:2 ). There are several pieces of evidence that the enhanced immune stimulating effect was due to the incorporation of unsaturated FAs in lipoproteins. First, the enhanced stimulation was dependent on Toll-like receptor 2 (TLR2). Second, an lgt mutant, unable to carry out lipidation of prolipoproteins, was unable to carry out immune stimulation when fed with unsaturated FAs. Third, the supplied FAs did not significantly affect growth, protein release, or expression of the model lipoprotein Lpl1. Although S. aureus is unable to synthesize unsaturated FAs, it incorporates long-chain unsaturated FAs into its lipoproteins, with the effect that the cells are better recognized by the innate immune system. This is an additional mechanism how our skin controls bacterial colonization and infection.
Leukocytes express formyl-peptide receptors (FPRs), which sense microbe-associated molecular pattern (MAMP) molecules, leading to leukocyte chemotaxis and activation. We recently demonstrated that phenol-soluble modulin (PSM) peptides from highly pathogenic are efficient ligands for the human FPR2. How PSM detection by FPR2 impacts on the course of infections has remained unknown. We characterized the specificity of mouse FPR2 (mFpr2) using a receptor-transfected cell line, homeobox b8 (Hoxb8), and primary neutrophils isolated from wild-type (WT) or mFpr2 mice. The influx of leukocytes into the peritoneum of WT and mFpr2 mice was analyzed. We demonstrate that mFpr2 is specifically activated by PSMs in mice, and they represent the first secreted pathogen-derived ligands for the mFpr2. Intraperitoneal infection with led to lower numbers of immigrated leukocytes in mFpr2 compared with WT mice at 3 h after infection, and this difference was not observed when mice were infected with an PSM mutant. Our data support the hypothesis that the mFpr2 is the functional homolog of the human FPR2 and that a mouse infection model represents a suitable model for analyzing the role of PSMs during infection. PSM recognition by mFpr2 shapes leukocyte influx in local infections, the typical infections caused by-Weiss, E., Hanzelmann, D., Fehlhaber, B., Klos, A., von Loewenich, F. D., Liese, J., Peschel, A., Kretschmer, D. Formyl-peptide receptor 2 governs leukocyte influx in local infections.
Toll-like receptor 2 (TLR2) is regarded as the major innate immunity sensor in infections caused by the Gram-positive bacterial pathogen Staphylococcus aureus. However, previous studies on the roles of TLR2 in S. aureus infections have been elusive and in part contradictory. It has remained particularly unclear if bacterial lipoproteins, the major TLR2 ligands, could serve as antigens with intrinsic adjuvant property for the development of protective vaccines. The study by Vu et al. published in this issue of Proteomics analyzed the antibody and T-cell responses in human sera against major S. aureus lipoproteins. Notably, even lipoproteins released to culture filtrates at similar levels as established immunodominant antigens elicited only very weak or no detectable antibody and T-cell responses, indicating that the potent TLR2-stimulating capacity of S. aureus lipoproteins does not promote and may rather impair robust immune responses so lipoprpteins. Among several potential explanations it is tempting to speculate that the role of TLR2 in S. aureus infections may be more complex and more ambiguous than previously thought. The study of Vu et al. may thus provoke more detailed investigations on the roles of lipoproteins and TLR2 in innate and adaptive immunity against bacterial pathogens.
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