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The function of TLR2 during staphylococcal diseases.

Fournier B - Front Cell Infect Microbiol (2013)

Bottom Line: However, the function of TLRs, and more particularly TLR2, during staphylococcal infections is still debated.In this review we will consider recent findings concerning the staphylococcal ligands sensed by TLR2 and more specifically the role of staphylococcal lipoproteins in TLR2 recognition.A new concept to emerge in recent years is that staphylococcal components must be phagocytosed and digested in the phagosome to be efficiently detected by the TLR2 of professional phagocytes.

View Article: PubMed Central - PubMed

Affiliation: Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine Atlanta, GA, USA. bfourni@emory.edu; bfournier15@yahoo.com

ABSTRACT
Staphylococcus aureus is a versatile pathogen causing a wide range of infections. It has been a major threat both in hospitals and in the community for decades. S. aureus is a pyogenic bacterium that elicits recruitment of polymorphonuclear leukocytes (neutrophils) to the site of infection. Neutrophils are among the first immune cells to migrate to an infection site attracted by chemoattractant gradients, usually initiated in response to inflammation. Neutrophil recruitment to an inflammation and/or infection site is a sophisticated process involving their interaction with endothelial and epithelial cells through adhesion molecules. Phagocytes have various receptors to detect pathogens, and they include Toll-like receptors (TLRs). TLRs have been extensively studied over the last 10 years and it is now established that they are critical during bacterial infections. However, the function of TLRs, and more particularly TLR2, during staphylococcal infections is still debated. In this review we will consider recent findings concerning the staphylococcal ligands sensed by TLR2 and more specifically the role of staphylococcal lipoproteins in TLR2 recognition. A new concept to emerge in recent years is that staphylococcal components must be phagocytosed and digested in the phagosome to be efficiently detected by the TLR2 of professional phagocytes. Neutrophils are an essential part of the immune response to staphylococcal infections, and in the second part of this review we will therefore describe the role of TLR2 in PMN recruitment in response to staphylococcal infections.

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Related in: MedlinePlus

Bacterial lipoproteins. (A) Structure of bacterial lipoproteins according to Braun and Wu (1994). The structure of synthetic lipopeptide Pam3CSK4 is also indicated. Triacylated bacterial lipoproteins and Pam3CSK4 have the same lipid moiety (green). R1, R2, and R3 are fatty acyl chains. Adapted from Braun and Wu (1994) and Chambaud et al. (1999). (B) Biosynthesis of lipoproteins in Gram-negative and Gram-positive bacteria. After crossing the cytoplasmic membrane Lgt (prolipoprotein diacylglyceryl transferase) transfers a diacylglyceride to the polypeptide chain and Lsp (lipoprotein signal peptidase) cleaves the signal peptide. In Gram-negative bacteria Lnt (lipoprotein N-acyl transferase) adds a third fatty acyl chain as indicated in the text. Although triacylated lipoproteins have been described in S. aureus, the mechanism of lipoprotein N-acylation is not known. Furthermore, in Gram-negative bacteria, acylated lipoproteins are translocated to the outer membrane by the Lol system [Reviewed in Okuda and Tokuda (2011)].
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Figure 1: Bacterial lipoproteins. (A) Structure of bacterial lipoproteins according to Braun and Wu (1994). The structure of synthetic lipopeptide Pam3CSK4 is also indicated. Triacylated bacterial lipoproteins and Pam3CSK4 have the same lipid moiety (green). R1, R2, and R3 are fatty acyl chains. Adapted from Braun and Wu (1994) and Chambaud et al. (1999). (B) Biosynthesis of lipoproteins in Gram-negative and Gram-positive bacteria. After crossing the cytoplasmic membrane Lgt (prolipoprotein diacylglyceryl transferase) transfers a diacylglyceride to the polypeptide chain and Lsp (lipoprotein signal peptidase) cleaves the signal peptide. In Gram-negative bacteria Lnt (lipoprotein N-acyl transferase) adds a third fatty acyl chain as indicated in the text. Although triacylated lipoproteins have been described in S. aureus, the mechanism of lipoprotein N-acylation is not known. Furthermore, in Gram-negative bacteria, acylated lipoproteins are translocated to the outer membrane by the Lol system [Reviewed in Okuda and Tokuda (2011)].

Mentions: TLR2 can recognize ligands with very diverse structures such as lipoproteins/lipopeptides, peptidoglycan, glycopolymers [lipoteichoic acid (LTA) and lipoarabinomannan], and proteins (porins, virus capsids) [reviewed in Zahringer et al. (2008) and Oliveira-Nascimento et al. (2012)]. The wide range of TLR2 ligands is partly due to its heterodimerization with co-receptors described to expand the spectrum of stimuli recognized by TLR2 without altering the signaling pathways used (Farhat et al., 2008). TLR2 associated with TLR1 senses triacyl lipopeptides/proteins (represented by the synthetic triacylated lipopeptide, Pam3-Cys-Ser-Lys4, Pam3CSK4) (Figure 1A) whereas an association with TLR6 is required to recognize diacyl lipoproteins (Pam2CSK4 or MALP2) (Ozinsky et al., 2000; Takeuchi et al., 2001, 2002; Takeda et al., 2002). Binding of Pam3CSK4 induces a conformational change of the ectodomains of both TLR1 and TLR2, resulting in the formation of a heterodimer. Pam2CSK4 does not promote this conformation and therefore does not activate TLR2-TLR1 (Jin et al., 2007). TLR2 may detect other staphylococcal PAMPs: peptidoglycan, a large polymer constituting the main component of the Gram-positive cell wall, and LTA (the counterpart of LPS in Gram-positive bacteria) [reviewed in Fournier and Philpott (2005)] although the relevance is controversial as the concentrations of peptidoglycan and LTA necessary to trigger TLR2 are not physiological (Zahringer et al., 2008). Indeed TLR2 recognition of peptidoglycan has been debated [(Travassos et al., 2004) and reviewed in Fournier and Philpott (2005)]. It has been suggested that muramyl dipeptide, the smallest peptidoglycan structure, is detected by an intracellular PRR, Nod2 (nucleotide-binding oligomerization domain protein 2) (Girardin et al., 2003). Interestingly, it was recently shown that peptidoglycan co-localizes with both TLR2 and Nod2 after internalization. Nevertheless, the interaction of peptidoglycan with TLR2 is not dependent on Nod2 and vice-versa (Muller-Anstett et al., 2010). Furthermore, peptidoglycan potentializes the activity of other TLR ligands, including LTA and LPS (Volz et al., 2010). Thus, it is possible that peptidoglycan is a weak TLR2 ligand that contributes to host immune responses by enhancing inflammation triggered by other more potent staphylococcal ligands such as lipoproteins. In addition to TLR1 and TLR6, other accessory non-TLR molecules may also serve as TLR2 co-receptors [reviewed in Oliveira-Nascimento et al. (2012)]. CD36, an integral membrane scavenger receptor, appears to have a role in LTA recognition and S. aureus phagocytosis (Hoebe et al., 2005; Stuart et al., 2005; Triantafilou et al., 2006; Baranova et al., 2008; Nilsen et al., 2008) although it is not clear how important this receptor is for the immune response against S. aureus (Baranova et al., 2008). CD36-deficient mice present an increased susceptibility to S. aureus and various TLR2 ligands including LTA and MALP2 (Hoebe et al., 2005). In contrast to other TLR2 accessory molecules, mannose-binding lectin (MBL) is a soluble humoral PRR that binds to the carbohydrate moieties of microorganisms in an EDTA-specific manner and in the case of S. aureus, LTA [reviewed in Ip et al. (2009)]. MBL-deficient mice are more susceptible than wild-type mice to S. aureus septicemia (Shi et al., 2004) and MBL has been reported to enhance S. aureus phagocytosis (Neth et al., 2002; Krarup et al., 2005; Ip et al., 2008). Indeed, the serum level of a wide array of cytokines (TNFα, RANTES, MIP-2, MCP-1, KC, IFNγ) is decreased in MBL-deficient mice compared to wild-type mice following S. aureus intravenous challenge (Ip et al., 2008). CD36 and MBL both bind to LTA but they interact independently with TLR2 (Ip et al., 2008).


The function of TLR2 during staphylococcal diseases.

Fournier B - Front Cell Infect Microbiol (2013)

Bacterial lipoproteins. (A) Structure of bacterial lipoproteins according to Braun and Wu (1994). The structure of synthetic lipopeptide Pam3CSK4 is also indicated. Triacylated bacterial lipoproteins and Pam3CSK4 have the same lipid moiety (green). R1, R2, and R3 are fatty acyl chains. Adapted from Braun and Wu (1994) and Chambaud et al. (1999). (B) Biosynthesis of lipoproteins in Gram-negative and Gram-positive bacteria. After crossing the cytoplasmic membrane Lgt (prolipoprotein diacylglyceryl transferase) transfers a diacylglyceride to the polypeptide chain and Lsp (lipoprotein signal peptidase) cleaves the signal peptide. In Gram-negative bacteria Lnt (lipoprotein N-acyl transferase) adds a third fatty acyl chain as indicated in the text. Although triacylated lipoproteins have been described in S. aureus, the mechanism of lipoprotein N-acylation is not known. Furthermore, in Gram-negative bacteria, acylated lipoproteins are translocated to the outer membrane by the Lol system [Reviewed in Okuda and Tokuda (2011)].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539681&req=5

Figure 1: Bacterial lipoproteins. (A) Structure of bacterial lipoproteins according to Braun and Wu (1994). The structure of synthetic lipopeptide Pam3CSK4 is also indicated. Triacylated bacterial lipoproteins and Pam3CSK4 have the same lipid moiety (green). R1, R2, and R3 are fatty acyl chains. Adapted from Braun and Wu (1994) and Chambaud et al. (1999). (B) Biosynthesis of lipoproteins in Gram-negative and Gram-positive bacteria. After crossing the cytoplasmic membrane Lgt (prolipoprotein diacylglyceryl transferase) transfers a diacylglyceride to the polypeptide chain and Lsp (lipoprotein signal peptidase) cleaves the signal peptide. In Gram-negative bacteria Lnt (lipoprotein N-acyl transferase) adds a third fatty acyl chain as indicated in the text. Although triacylated lipoproteins have been described in S. aureus, the mechanism of lipoprotein N-acylation is not known. Furthermore, in Gram-negative bacteria, acylated lipoproteins are translocated to the outer membrane by the Lol system [Reviewed in Okuda and Tokuda (2011)].
Mentions: TLR2 can recognize ligands with very diverse structures such as lipoproteins/lipopeptides, peptidoglycan, glycopolymers [lipoteichoic acid (LTA) and lipoarabinomannan], and proteins (porins, virus capsids) [reviewed in Zahringer et al. (2008) and Oliveira-Nascimento et al. (2012)]. The wide range of TLR2 ligands is partly due to its heterodimerization with co-receptors described to expand the spectrum of stimuli recognized by TLR2 without altering the signaling pathways used (Farhat et al., 2008). TLR2 associated with TLR1 senses triacyl lipopeptides/proteins (represented by the synthetic triacylated lipopeptide, Pam3-Cys-Ser-Lys4, Pam3CSK4) (Figure 1A) whereas an association with TLR6 is required to recognize diacyl lipoproteins (Pam2CSK4 or MALP2) (Ozinsky et al., 2000; Takeuchi et al., 2001, 2002; Takeda et al., 2002). Binding of Pam3CSK4 induces a conformational change of the ectodomains of both TLR1 and TLR2, resulting in the formation of a heterodimer. Pam2CSK4 does not promote this conformation and therefore does not activate TLR2-TLR1 (Jin et al., 2007). TLR2 may detect other staphylococcal PAMPs: peptidoglycan, a large polymer constituting the main component of the Gram-positive cell wall, and LTA (the counterpart of LPS in Gram-positive bacteria) [reviewed in Fournier and Philpott (2005)] although the relevance is controversial as the concentrations of peptidoglycan and LTA necessary to trigger TLR2 are not physiological (Zahringer et al., 2008). Indeed TLR2 recognition of peptidoglycan has been debated [(Travassos et al., 2004) and reviewed in Fournier and Philpott (2005)]. It has been suggested that muramyl dipeptide, the smallest peptidoglycan structure, is detected by an intracellular PRR, Nod2 (nucleotide-binding oligomerization domain protein 2) (Girardin et al., 2003). Interestingly, it was recently shown that peptidoglycan co-localizes with both TLR2 and Nod2 after internalization. Nevertheless, the interaction of peptidoglycan with TLR2 is not dependent on Nod2 and vice-versa (Muller-Anstett et al., 2010). Furthermore, peptidoglycan potentializes the activity of other TLR ligands, including LTA and LPS (Volz et al., 2010). Thus, it is possible that peptidoglycan is a weak TLR2 ligand that contributes to host immune responses by enhancing inflammation triggered by other more potent staphylococcal ligands such as lipoproteins. In addition to TLR1 and TLR6, other accessory non-TLR molecules may also serve as TLR2 co-receptors [reviewed in Oliveira-Nascimento et al. (2012)]. CD36, an integral membrane scavenger receptor, appears to have a role in LTA recognition and S. aureus phagocytosis (Hoebe et al., 2005; Stuart et al., 2005; Triantafilou et al., 2006; Baranova et al., 2008; Nilsen et al., 2008) although it is not clear how important this receptor is for the immune response against S. aureus (Baranova et al., 2008). CD36-deficient mice present an increased susceptibility to S. aureus and various TLR2 ligands including LTA and MALP2 (Hoebe et al., 2005). In contrast to other TLR2 accessory molecules, mannose-binding lectin (MBL) is a soluble humoral PRR that binds to the carbohydrate moieties of microorganisms in an EDTA-specific manner and in the case of S. aureus, LTA [reviewed in Ip et al. (2009)]. MBL-deficient mice are more susceptible than wild-type mice to S. aureus septicemia (Shi et al., 2004) and MBL has been reported to enhance S. aureus phagocytosis (Neth et al., 2002; Krarup et al., 2005; Ip et al., 2008). Indeed, the serum level of a wide array of cytokines (TNFα, RANTES, MIP-2, MCP-1, KC, IFNγ) is decreased in MBL-deficient mice compared to wild-type mice following S. aureus intravenous challenge (Ip et al., 2008). CD36 and MBL both bind to LTA but they interact independently with TLR2 (Ip et al., 2008).

Bottom Line: However, the function of TLRs, and more particularly TLR2, during staphylococcal infections is still debated.In this review we will consider recent findings concerning the staphylococcal ligands sensed by TLR2 and more specifically the role of staphylococcal lipoproteins in TLR2 recognition.A new concept to emerge in recent years is that staphylococcal components must be phagocytosed and digested in the phagosome to be efficiently detected by the TLR2 of professional phagocytes.

View Article: PubMed Central - PubMed

Affiliation: Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine Atlanta, GA, USA. bfourni@emory.edu; bfournier15@yahoo.com

ABSTRACT
Staphylococcus aureus is a versatile pathogen causing a wide range of infections. It has been a major threat both in hospitals and in the community for decades. S. aureus is a pyogenic bacterium that elicits recruitment of polymorphonuclear leukocytes (neutrophils) to the site of infection. Neutrophils are among the first immune cells to migrate to an infection site attracted by chemoattractant gradients, usually initiated in response to inflammation. Neutrophil recruitment to an inflammation and/or infection site is a sophisticated process involving their interaction with endothelial and epithelial cells through adhesion molecules. Phagocytes have various receptors to detect pathogens, and they include Toll-like receptors (TLRs). TLRs have been extensively studied over the last 10 years and it is now established that they are critical during bacterial infections. However, the function of TLRs, and more particularly TLR2, during staphylococcal infections is still debated. In this review we will consider recent findings concerning the staphylococcal ligands sensed by TLR2 and more specifically the role of staphylococcal lipoproteins in TLR2 recognition. A new concept to emerge in recent years is that staphylococcal components must be phagocytosed and digested in the phagosome to be efficiently detected by the TLR2 of professional phagocytes. Neutrophils are an essential part of the immune response to staphylococcal infections, and in the second part of this review we will therefore describe the role of TLR2 in PMN recruitment in response to staphylococcal infections.

Show MeSH
Related in: MedlinePlus