Host defenses against<i>Staphylococcus aureus</i>infection require recognition of bacterial lipoproteins

Wardenburg, Juliane Bubeck; Williams, Wade A.; Missiakas, Dominique

doi:10.1073/pnas.0603072103

Cited by 230 publications

(233 citation statements)

References 42 publications

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“…However, the diversity, relative importance, and variability of proinflammatory staphylococcal molecules, such as peptidoglycan, lipopeptides, lipoteichoic acid, formylated peptides, and others have remained uncertain. While the relative importance of lipoproteins and formylated peptides has recently been confirmed using defined mutants lacking the corresponding classes of molecules (6,9,25), such a strategy is impossible for PG, which is essential for bacterial viability. However, bacterial mutants with altered PG structures might help to investigate the relative role of PG, along with the modulation of PG structure.…”

Section: Proinflammatory Capacities Of Synthetic Mdps With or Withoutmentioning

confidence: 99%

Muropeptide Modification-Amidation of Peptidoglycand-Glutamate Does Not Affect the Proinflammatory Activity ofStaphylococcus aureus

et al. 2007

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Peptidoglycan muropeptides, potent proinflammatory components, are amidated in Staphylococcus aureus for unknown reasons. To study whether this modification may modulate proinflammatory capacity, cytokine induction by isogenic S. aureus strains with different amidation levels and by synthetic amidated/nonamidated muramyldipeptides was evaluated. However, amidation did not significantly affect cytokine induction. This finding contributes to defining peptidoglycan receptor specificities and indicates that further rationales for muropeptide amidation have to be considered.Staphylococcus aureus is a frequent constituent of human nasal microflora and a major cause of severe endogenous infections (11). The staphylococcal cell wall determines several key aspects of the infection process, such as adherence (11, 28), immune recognition (13), and resistance to host defenses (21,22). While many adhesive surface proteins have been investigated (12), the structure, function, and variability of nonproteinaceous polymers, such as peptidoglycan (PG) or teichoic acids, have remained parts of a neglected field of research. S. aureus is known to modify the canonical PG structure by O acetylation of the glycan strand and by amidation of the ␣-carboxyl group of the D-glutamate (D-Glu) residue in muropeptides, resulting in the formation of D-isoglutamine (16, 29). While O acetylation confers lysozyme resistance (3), the primary role of D-Glu amidation has remained unclear. Nevertheless, the latter modification is known to affect the level of methicillin resistance (4, 17) and to contribute to vancomycin susceptibility in S. aureus (8). The amino group for D-Glu amidation in S. aureus muropeptides is most probably derived from free glutamine (17, 23). However, the responsible transamidase enzyme has not yet been identified. Gustafson et al. described a femC mutant with 48% decreased muropeptide amidation (17, 26). The femC mutant has a disrupted glnR gene encoding the regulator of the glutamine synthetase (Fig. 1A), which results in reduced glutamine synthetase activity. As a consequence of lower amounts of the amino group donor, muropeptide amidation is reduced in this mutant (17).PG has potent proinflammatory properties (5). It is sensed by the human innate immune system via NOD1 or NOD2 proteins (15,18). An additional role of the TLR2 receptor in PG sensing has been described previously (10) but remains a matter of debate (27). The minimal structure required for NOD1 recognition is a dipeptide consisting of D-Glu and meso-diaminopimelate (mesoDAP), which is mainly produced by gram-negative bacteria (14, 15). D-Glu amidation (leading to D-isoglutamine) strongly impairs PG recognition by NOD1 (7), and the amidation of mesoDAP completely abrogates the ability of NOD1 to detect PG (15). NOD2 has a different substrate specificity as it requires a muramyldipeptide (MDP) composed of N-acetylmuramic acid, L-alanine, and D-Glu (Fig. 1B) (19,27). S. aureus PG is recognized by NOD2 but not by NOD1 since it contains L-lysine instead of meso-D...

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Section: Proinflammatory Capacities Of Synthetic Mdps With or Withoutmentioning

confidence: 99%

Muropeptide Modification-Amidation of Peptidoglycand-Glutamate Does Not Affect the Proinflammatory Activity ofStaphylococcus aureus

et al. 2007

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“…The former study [47] is particularly notable as the lgt mutant was attenuated in a mouse infection model. Second, lgt mutants of S. agalactiae [29] and Staphylococcus aureus [49] exhibit hypervirulent phenotypes in mouse models of infection. These phenotypes most likely reflect the failure of nonlipidated lipoprotein precursors to elicit protective immune responses [49][50][51] possibly because of their inability to activate Toll-like receptor 2-mediated signalling [29].…”

Section: Role Of Lgt and Lsp In Virulence Of Gram-positive Pathogensmentioning

confidence: 99%

“…Second, lgt mutants of S. agalactiae [29] and Staphylococcus aureus [49] exhibit hypervirulent phenotypes in mouse models of infection. These phenotypes most likely reflect the failure of nonlipidated lipoprotein precursors to elicit protective immune responses [49][50][51] possibly because of their inability to activate Toll-like receptor 2-mediated signalling [29]. By contrast, an lgt mutant of Listeria monocytogenes was attenuated in a mouse infection model even though the mutant failed to activate Toll-like receptor 2-mediated immune responses [52].…”

Section: Role Of Lgt and Lsp In Virulence Of Gram-positive Pathogensmentioning

confidence: 99%

Lipoprotein biogenesis in Gram-positive bacteria: knowing when to hold ‘em, knowing when to fold ‘em

Hutchings

Palmer

Harrington

et al. 2009

Trends in Microbiology

181

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“…Loss of Lgt or Lsp leads to attenuation of virulence in Streptococcus pneumoniae (Petit et al, 2001), to a decrease in immune activation for group B Streptococcus, Staphylococcus aureus and Listeria monocytogenes (Henneke et al, 2008;Stoll et al, 2005;Machata et al, 2008), and to a reduction in adherence of Streptococcus agalactiae (Bray et al, 2009) and in intracellular growth of L. monocytogenes (Baumgärtner et al, 2007). While S. agalactiae and Staphylococcus aureus lgt mutants show increased sensitivity to oxidative stress (Bray et al, 2009) and growth attenuation in whole human blood (Stoll et al, 2005), respectively, both display a hypervirulent phenotype (Henneke et al, 2008;Bubeck Wardenburg et al, 2006). In E. faecalis, transport of lipoproteins across the membrane uses the Sec system, as no Tat mechanism is present and none of the 90 lipoproteins predicted in E. faecalis V583 harbours a Tat signal peptide (Reffuveille et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

The prolipoprotein diacylglyceryl transferase (Lgt) of Enterococcus faecalis contributes to virulence

et al. 2012

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Enterococcus faecalis is an opportunistic pathogen responsible for nosocomial infections. Lipoproteins in Gram-positive bacteria are translocated across the plasma membrane and anchored by the fatty acid group. They perform critical roles, with some described as virulence determinants. The aim of this study was to explore the roles of E. faecalis lipoproteins in the stress response and virulence. We constructed a mutant affected in the predicted prolipoprotein diacylglyceryl transferase gene lgt, and examined the role of Lgt in membrane anchoring, growth, the stress response and virulence. Inactivation of lgt enhanced growth in a high concentration of Mn2+ or under oxidative stress in vitro, and significantly decreased virulence

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Host defenses againstStaphylococcus aureusinfection require recognition of bacterial lipoproteins

Cited by 230 publications

References 42 publications

Muropeptide Modification-Amidation of Peptidoglycand-Glutamate Does Not Affect the Proinflammatory Activity ofStaphylococcus aureus

Muropeptide Modification-Amidation of Peptidoglycand-Glutamate Does Not Affect the Proinflammatory Activity ofStaphylococcus aureus

Lipoprotein biogenesis in Gram-positive bacteria: knowing when to hold ‘em, knowing when to fold ‘em

The prolipoprotein diacylglyceryl transferase (Lgt) of Enterococcus faecalis contributes to virulence

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