Andreas Peschel

University of Tuebingen, Tübingen, Baden-Württemberg, Germany

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Publications (143)784.83 Total impact

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    ABSTRACT: The cotton rat nose is commonly used as a model for Staphylococcus aureus colonization, as it is both physiologically and anatomically comparable to the human nares and can be easily colonized by this organism. However, while the colonization of the human anterior nares has been extensively studied, the microbial community structure of cotton rat noses has not been reported so far. We describe here the microbial community structure of the cotton rat (Sigmodon hispidus) nose through next generation sequencing of 16S rRNA gene amplicons covering the V1-V2 region and the analysis of nearly full length 16S rRNA genes of the major phylotypes. Roughly half of the microbial community was composed of two undescribed species of the genus Campylobacter, with phylotypes belonging to the genera Catonella, Acholeplasma, Streptobacillus and Capnocytophaga constituting the predominant community members. Thus, the nasal community of the cotton rat is uniquely composed of several novel bacterial species and may not reflect the complex interactions that occur in human anterior nares. Mammalian airway microbiota may, however, be a rich source of hitherto unknown microbes. This article is protected by copyright. All rights reserved.
    Environmental Microbiology Reports 08/2015; DOI:10.1111/1758-2229.12334 · 3.29 Impact Factor
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    ABSTRACT: The cell envelopes of many Gram-positive bacteria contain wall teichoic acids (WTA). Staphylococcus aureus WTAs are composed of ribitol phosphate (RboP) or glycerol phosphate (GroP) backbones substituted with D-alanine and N-acetyl-D-glucosamine (GlcNAc) or N-acetyl-D-galactosamine (GalNAc). Two WTA glycosyltransferases, TarM and TarS, are responsible for modifying RboP WTA with α-GlcNAc and β-GlcNAc, respectively. Recently we reported that purified human serum anti-WTA IgG specifically recognizes β-GlcNAc of staphylococcal RboP WTA and then facilitates complement C3 deposition and opsonophagocytosis of S. aureus laboratory strains. This prompted us to examine whether anti-WTA IgG can induce C3 deposition on a diverse set of clinical S. aureus isolates. To this end, we compared anti-WTA IgG-mediated C3 deposition and opsonophagocytosis abilities using 13 different staphylococcal strains. Of note the majority of S. aureus strains tested was recognized by anti-WTA IgG, resulting in C3 deposition and opsonophagocytosis. A minority of strains was not recognized by anti-WTA IgG, which correlated either with extensive capsule production or alteration in the WTA glycosylation pattern. Our results demonstrate that the presence of TarS-mediated β-GlcNAcylated WTA in clinically isolated S. aureus strains is an important factor for induction of anti-WTA IgG-mediated C3 deposition and opsonophagocytosis. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Infection and immunity 08/2015; DOI:10.1128/IAI.00767-15 · 3.73 Impact Factor
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    ABSTRACT: Abstract Nasal colonization by the human pathogen Staphylococcus aureus is a major risk factor for hospital- and community-acquired infections. A key factor required for nasal colonization is a cell surface-exposed zwitterionic glycopolymer, termed wall teichoic acid (WTA). However, the precise mechanisms that govern WTA-mediated nasal colonization have remained elusive. Here, we report that WTA GlcNAcylation is a pivotal requirement for WTA-dependent attachment of community-acquired methicillin-resistant S. aureus (MRSA) and emerging livestock-associated MRSA to human nasal epithelial cells, even under conditions simulating the nutrient composition and dynamic flow of nasal secretions. Depending on the S. aureus strain, WTA O-GlcNAcylation occurs in either α or β configuration, which have similar capacities to mediate attachment to human nasal epithelial cells, suggesting that many S. aureus strains maintain redundant pathways to ensure appropriate WTA glycosylation. Strikingly, a lack of WTA glycosylation significantly abrogated the ability of MRSA to colonize cotton rat nares in vivo. These results indicate that WTA glycosylation modulates S. aureus nasal colonization and may help to develop new strategies for eradicating S. aureus nasal colonization in the future.
    mBio 06/2015; 6(4)(4). DOI:10.1128/mBio.00632-15. · 6.79 Impact Factor
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    ABSTRACT: Most staphylococci produce short α-type PSMs and about twice as long β-type PSMs that are potent leukocyte attractants and toxins. PSMs are usually secreted with the N-terminal formyl group but are only weak agonists for the leukocyte FPR1. Instead, the FPR1-related FPR2 senses PSMs efficiently and is crucial for leukocyte recruitment in infection. Which structural features distinguish FPR1 from FPR2 ligands has remained elusive. To analyze which peptide properties may govern the capacities of β-type PSMs to activate FPRs, full-length and truncated variants of such peptides from Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus lugdunensis were synthesized. FPR2 activation was observed even for short N- or C-terminal β-type PSM variants once they were longer than 18 aa, and this activity increased with length. In contrast, the shortest tested peptides were potent FPR1 agonists, and this property declined with increasing peptide length. Whereas full-length β-type PSMs formed α-helices and exhibited no FPR1-specific activity, the truncated peptides had less-stable secondary structures, were weak agonists for FPR1, and required N-terminal formyl-methionine residues to be FPR2 agonists. Together, these data suggest that FPR1 and FPR2 have opposed ligand preferences. Short, flexible PSM structures may favor FPR1 but not FPR2 activation, whereas longer peptides with α-helical, amphipathic properties are strong FPR2 but only weak FPR1 agonists. These findings should help to unravel the ligand specificities of 2 critical human PRRs, and they may be important for new, anti-infective and anti-inflammatory strategies. © Society for Leukocyte Biology.
    Journal of Leukocyte Biology 02/2015; 97(4). DOI:10.1189/jlb.2A0514-275R · 4.29 Impact Factor
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    ABSTRACT: Anionic glycopolymers known as wall teichoic acids (WTAs) functionalize the peptidoglycan layers of many Gram-positive bacteria. WTAs play central roles in many fundamental aspects of bacterial physiology, and they are important determinants of pathogenesis and antibiotic resistance. A number of enzymes that glycosylate WTA in S. aureus have recently been identified. Among these is the glycosyltransferase TarM, a component of the WTA de-novo biosynthesis pathway. TarM performs the synthesis of α-O-N-acetylglycosylated poly-5'-phosphoribitol in the WTA structure. We have solved the crystal structure of TarM at 2.4 Å resolution, and we have also determined a structure of the enzyme in complex with its substrate UDP-GlcNAc at 2.8 Å resolution. The protein assembles into a propeller-like homotrimer, in which each blade contains a GT-B-type glycosyltransferase domain with a typical Rossmann fold. The enzymatic reaction retains the stereochemistry of the anomeric center of the transferred GlcNAc-moiety on the polyribitol backbone. TarM assembles into a trimer using a novel trimerization domain, here termed the HUB domain. Structure-guided mutagenesis experiments of TarM identify residues critical for enzyme activity, assign a putative role for the HUB in TarM function, and allow us to propose a likely reaction mechanism. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 02/2015; 290(15). DOI:10.1074/jbc.M114.619924 · 4.57 Impact Factor
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    ABSTRACT: Phospholipids are synthesized at the inner leaflet of the bacterial cytoplasmic membrane but have to be translocated to the outer leaflet to maintain membrane lipid bilayer composition and structure. Even though phospholipid flippases have been proposed to exist in bacteria, only one such protein, MprF, has been described. MprF is a large integral membrane protein found in several prokaryotic phyla, whose C terminus modifies phosphatidylglycerol (PG), the most common bacterial phospholipid, with lysine or alanine to modulate the membrane surface charge and, as a consequence, confer resistance to cationic antimicrobial agents such as daptomycin. In addition, MprF is a flippase for the resulting lipids, Lys-PG or Ala-PG. Here we demonstrate that the flippase activity resides in the N-terminal 6 to 8 transmembrane segments of the Staphylococcus aureus MprF and that several conserved, charged amino acids and a proline residue are crucial for flippase function. MprF protects S. aureus against the membrane-active antibiotic daptomycin only when both domains are present, but the two parts do not need to be covalently linked and can function in trans. The Lys-PG synthase and flippase domains were each found to homo-oligomerize and also to interact with each other, which illustrates how the two functional domains may act together. Moreover, full-length MprF proteins formed oligomers, indicating that MprF functions as a dimer or larger oligomer. Together our data reveal how bacterial phospholipid flippases may function in the context of lipid biosynthetic processes. IMPORTANCE : Bacterial cytoplasmic membranes are crucial for maintaining and protecting cellular integrity. For instance, they have to cope with membrane-damaging agents such as cationic antimicrobial peptides (CAMPs) produced by competing bacteria (bacteriocins), secreted by eukaryotic host cells (defensins), or used as antimicrobial therapy (daptomycin). The MprF protein is found in many Gram-positive, Gram-negative, and even archaeal commensals or pathogens and confers resistance to CAMPs by modifying anionic phospholipids with amino acids, thereby compromising the membrane interaction of CAMPs. Here we describe how MprF does not only modify phospholipids but uses an additional, distinct domain for translocating the resulting lysinylated phospholipids to the outer leaflet of the membrane. We reveal critical details for the structure and function of MprF, the first dedicated prokaryotic phospholipid flippase, which may pave the way for targeting MprF with new antimicrobials that would not kill bacteria but sensitize them to antibiotics and innate host defense molecules. Copyright © 2015 Ernst et al.
    mBio 01/2015; 6(1). DOI:10.1128/mBio.02340-14 · 6.79 Impact Factor
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    ABSTRACT: Genetic manipulation of emerging bacterial pathogens such as coagulase-negative staphylococci (CoNS) is a major hurdle in clinical and basic microbiological research. Strong genetic barriers such as restriction modification systems or clustered regularly interspaced short palindromic repeats (CRISPR) usually interfere with available techniques for DNA transformation and therefore complicate or render manipulation of CoNS impossible. Thus, current knowledge on pathogenicity and virulence determinants of CoNS is very limited. Here, a rapid, efficient and highly reliable technique is presented to transfer plasmid DNA essential for genetic engineering to important CoNS pathogens from a unique Staphylococcus aureus strain via a specific S. aureus bacteriophage Φ187. Even strains refractory to electroporation can be transduced by this technique once donor and recipient strains share similar Φ187 receptor properties. As a proof of principle, this technique was used to delete the alternative transcription factor sigma B (SigB) via allelic replacement in nasal and clinical Staphylococcus epidermidis isolates at high efficiencies. The described approach will allow for the genetic manipulation of a wide range of CoNS pathogens and might inspire research activities to manipulate other important pathogens in a similar fashion. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Applied and Environmental Microbiology 01/2015; 81(7). DOI:10.1128/AEM.04190-14 · 3.67 Impact Factor
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    ABSTRACT: Both Staphylococcus aureus and Staphylococcus epidermidis can form biofilms on natural surfaces or abiotic surfaces, such as medical implants, resulting in biofilm-associated diseases that are refractory to antibiotic treatment. We previously reported a promising antibacterial compound (Compound 2) and its derivatives with bactericidal and anti-biofilm activities against both S. epidermidis and S. aureus. We have further evaluated the antibacterial activities of four Compound 2 derivatives (H2-38, H2-39, H2-74 and H2-81) against 163 clinical strains of S. epidermidis and S. aureus, including methicillin-susceptible and methicillin-resistant strains, as well as biofilm-forming and non-biofilm-forming strains. The four derivatives inhibited the planktonic growth of all of the clinical staphylococcal isolates, including methicillin-resistant S. aureus and methicillin-resistant S. epidermidis and displayed bactericidal activities against both immature (6 h) and mature (24 h) biofilms formed by the strong biofilm-forming strains. The derivatives, which all target YycG, will help us to develop new antimicrobial agents against multidrug-resistant staphylococci infections and biofilm-associated diseases.
    Emerging Microbes and Infections 01/2015; 4(1):e1. DOI:10.1038/emi.2015.1 · 2.26 Impact Factor
  • Sebastian Kuhn · Christoph J Slavetinsky · Andreas Peschel
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    ABSTRACT: Phospholipids are the major components of bacterial membranes, and changes in phospholipid composition affect important cellular processes such as metabolism, stress response, antimicrobial resistance, and virulence. The most prominent phospholipids in Staphylococcus aureus are phosphatidylglycerol, lysyl-phosphatidylglycerol, and cardiolipin, whose biosynthesis is mediated by a complex protein machinery. Phospholipid composition of the staphylococcal membrane has to be continuously adjusted to changing external conditions, which is achieved by a series of transcriptional and biochemical regulatory mechanisms. This mini-review outlines the current state of knowledge concerning synthesis, regulation, and function of the major staphylococcal phospholipids. Copyright © 2015. Published by Elsevier GmbH.
    International Journal of Medical Microbiology 12/2014; 305(2). DOI:10.1016/j.ijmm.2014.12.016 · 3.61 Impact Factor
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    ABSTRACT: The innate immune system recognizes conserved microorganism-associated molecular patterns (MAMPs), some of which are sensed by G protein-coupled receptors (GPCRs), and this leads to chemotactic leukocyte influx. Recent studies have indicated that these processes are crucial for host defence and rely on a larger set of chemotactic MAMPs and corresponding GPCRs than was previously thought. Agonists, such as bacterial formyl peptides, enterococcal pheromone peptides, staphylococcal peptide toxins, bacterial fermentation products and the Helicobacter pylori peptide HP(2-20), stimulate specific GPCRs. The importance of leukocyte chemotaxis in host defence is highlighted by the fact that some bacterial pathogens produce chemotaxis inhibitors. How the various chemoattractants, receptors and antagonists shape antibacterial host defence represents an important topic for future research.
    Nature Reviews Microbiology 12/2014; 13(2). DOI:10.1038/nrmicro3390 · 23.57 Impact Factor
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    ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of morbidity and death. Phenol-soluble modulins (PSMs) are recently-discovered toxins with a key impact on the development of Staphylococcus aureus infections. Allelic variants of PSMs and their potential impact on pathogen success during infection have not yet been described. Here we show that the clonal complex (CC) 30 lineage, a major cause of hospital-associated sepsis and hematogenous complications, expresses an allelic variant of the PSMα3 peptide. We found that this variant, PSMα3N22Y, is characteristic of CC30 strains and has significantly reduced cytolytic and pro-inflammatory potential. Notably, CC30 strains showed reduced cytolytic and chemotactic potential toward human neutrophils, and increased hematogenous seeding in a bacteremia model, compared to strains in which the genome was altered to express non-CC30 PSMα3. Our findings describe a molecular mechanism contributing to attenuated pro-inflammatory potential in a main MRSA lineage. They suggest that reduced pathogen recognition via PSMs allows the bacteria to evade elimination by innate host defenses during bloodstream infections. Furthermore, they underscore the role of point mutations in key S. aureus toxin genes in that adaptation and the pivotal importance PSMs have in defining key S. aureus immune evasion and virulence mechanisms.
    PLoS Pathogens 08/2014; 10(8):e1004298. DOI:10.1371/journal.ppat.1004298 · 7.56 Impact Factor
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    ABSTRACT: Rapid diagnosis is essential for the management of Staphylococcus aureus infections. A host recognition protein from S. aureus bacteriophage phiSLT was recombinantly produced and used to coat streptavidin latex beads to develop a latex agglutination test (LAT). The diagnostic accuracy of this bacteriophage-based test was compared with that of a conventional LAT, Pastorex Staph-Plus, by investigating a clinical collection of 86 S. aureus isolates and 128 coagulase-negative staphylococci (CoNS) from deep tissue infections. All of the clinical S. aureus isolates were correctly identified by the bacteriophage-based test. While most of the CoNS were correctly identified as non-S. aureus isolates, 7.9% of the CoNS caused agglutination. Thus, the sensitivity of the bacteriophage-based LAT for identification of S. aureus among clinical isolates was 100%, its specificity was 92.1%, its positive predictive value (PPV) was 89.6%, and its negative predictive value (NPV) was 100%. The sensitivity, specificity, PPV, and NPV of the Pastorex LAT for the identification of S. aureus were 100%, 99.2%, 98.9%, and 100%, respectively. Among the additionally tested 35 S. aureus and 91 non-S. aureus staphylococcal reference and type strains, 1 isolate was false negative by each system; 13 and 8 isolates were false positive by the bacteriophage-based and Pastorex LATs, respectively. The ability of the phiSLT protein to detect S. aureus was dependent on the presence of wall teichoic acid (WTA) and corresponded to the production of ribitol phosphate WTA, which is found in most S. aureus clones but only a small minority of CoNS. Bacteriophage-based LAT identification is a promising strategy for rapid pathogen identification. Finding more specific bacteriophage proteins would increase the specificity of this novel diagnostic approach.
    Journal of Clinical Microbiology 07/2014; 52(9). DOI:10.1128/JCM.01432-14 · 3.99 Impact Factor
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    Volker Winstel · Guoqing Xia · Andreas Peschel
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    ABSTRACT: The thick peptidoglycan layers of Gram-positive bacteria are connected to polyanionic glycopolymers called wall teichoic acids (WTA). Pathogens such as Staphylococcus aureus, Listeria monocytogenes, or Enterococcus faecalis produce WTA with diverse, usually strain-specific structure. Extensive studies on S. aureus WTA mutants revealed important functions of WTA in cell division, growth, morphogenesis, resistance to antimicrobials, and interaction with host or phages. While most of the S. aureus WTA-biosynthetic genes have been identified it remained unclear for long how and why S. aureus glycosylates WTA with α- or β-linked N-acetylglucosamine (GlcNAc). Only recently the discovery of two WTA glycosyltransferases, TarM and TarS, yielded fundamental insights into the roles of S. aureus WTA glycosylation. Mutants lacking WTA GlcNAc are resistant towards most of the S. aureus phages and, surprisingly, TarS-mediated WTA β-O-GlcNAc modification is essential for β-lactam resistance in methicillin-resistant S. aureus. WTA glycosylation with a variety of sugars and corresponding glycosyltransferases were also identified in other Gram-positive bacteria, which paves the way for detailed investigations on the diverse roles of WTA modification with sugar residues.
    International Journal of Medical Microbiology 05/2014; 304(3-4):215-2221. DOI:10.1016/j.ijmm.2013.10.009 · 3.61 Impact Factor
  • 41st Annual Meeting of the Arbeitsgemeinschaft-Dermatologische-Forschung; 03/2014
  • 41st Annual Meeting of the Arbeitsgemeinschaft-Dermatologische-Forschung; 03/2014
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    ABSTRACT: The major clonal lineages of the human pathogen Staphylococcus aureus produce cell wall-anchored anionic poly-ribitol-phosphate (RboP) wall teichoic acids (WTA) substituted with d-Alanine and N-acetyl-d-glucosamine. The phylogenetically isolated S. aureus ST395 lineage has recently been found to produce a unique poly-glycerol-phosphate (GroP) WTA glycosylated with N-acetyl-d-galactosamine (GalNAc). ST395 clones bear putative WTA biosynthesis genes on a novel genetic element probably acquired from coagulase-negative staphylococci (CoNS). We elucidated the ST395 WTA biosynthesis pathway and identified three novel WTA biosynthetic genes, including those encoding an α-O-GalNAc transferase TagN, a nucleotide sugar epimerase TagV probably required for generation of the activated sugar donor substrate for TagN, and an unusually short GroP WTA polymerase TagF. By using a panel of mutants derived from ST395, the GalNAc residues carried by GroP WTA were found to be required for infection by the ST395-specific bacteriophage Φ187 and to play a crucial role in horizontal gene transfer of S. aureus pathogenicity islands (SaPIs). Notably, ectopic expression of ST395 WTA biosynthesis genes rendered normal S. aureus susceptible to Φ187 and enabled Φ187-mediated SaPI transfer from ST395 to regular S. aureus. We provide evidence that exchange of WTA genes and their combination in variable, mosaic-like gene clusters have shaped the evolution of staphylococci and their capacities to undergo horizontal gene transfer events.
    mBio 02/2014; 5(2). DOI:10.1128/mBio.00869-14 · 6.79 Impact Factor
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    ABSTRACT: Colonization of the human nose by Staphylococcus aureus in one-third of the population represents a major risk factor for invasive infections. The basis for adaptation of S. aureus to this specific habitat and reasons for the human predisposition to become colonized have remained largely unknown. Human nasal secretions were analyzed by metabolomics and found to contain potential nutrients in rather low amounts. No significant differences were found between S. aureus carriers and non-carriers, indicating that carriage is not associated with individual differences in nutrient supply. A synthetic nasal medium (SNM3) was composed based on the metabolomics data that permits consistent growth of S. aureus isolates. Key genes were expressed in SNM3 in a similar way as in the human nose, indicating that SNM3 represents a suitable surrogate environment for in vitro simulation studies. While the majority of S. aureus strains grew well in SNM3, most of the tested coagulase-negative staphylococci (CoNS) had major problems to multiply in SNM3 supporting the notion that CoNS are less well adapted to the nose and colonize preferentially the human skin. Global gene expression analysis revealed that, during growth in SNM3, S. aureus depends heavily on de novo synthesis of methionine. Accordingly, the methionine-biosynthesis enzyme cysteine-γ-synthase (MetI) was indispensable for growth in SNM3, and the MetI inhibitor DL-propargylglycine inhibited S. aureus growth in SNM3 but not in the presence of methionine. Of note, metI was strongly up-regulated by S. aureus in human noses, and metI mutants were strongly abrogated in their capacity to colonize the noses of cotton rats. These findings indicate that the methionine biosynthetic pathway may include promising antimicrobial targets that have previously remained unrecognized. Hence, exploring the environmental conditions facultative pathogens are exposed to during colonization can be useful for understanding niche adaptation and identifying targets for new antimicrobial strategies.
    PLoS Pathogens 01/2014; 10(1):e1003862. DOI:10.1371/journal.ppat.1003862 · 7.56 Impact Factor
  • 14th European Meeting on Complement in Human Disease; 12/2013
  • Andreas Peschel · Michael Otto
    Nature Reviews Microbiology 11/2013; 11(11). DOI:10.1038/nrmicro3151 · 23.57 Impact Factor
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    ABSTRACT: Serum antibodies and mannose-binding lectin (MBL) are important host-defense factors for host adaptive and innate immunity, respectively. Antibodies and MBL also initiate the classical and lectin complement pathways, respectively, leading to opsonophagocytosis. We have previously shown that Staphylococcus aureus wall teichoic acid (WTA), a cell wall glycopolymer consisting of ribitol phosphate substituted with α- or β-O-N-acetyl-D-glucosamine (GlcNAc) and D-alanine, is recognized by MBL and serum anti-WTA IgG. However, the exact antigenic determinants to which anti-WTA antibodies or MBL bind have not been determined. To answer this question, several S. aureus mutants, such as α-GlcNAc glycosyl- transferase-deficient S. aureus ΔtarM, β-GlcNAc glycosyltransferase-deficient ΔtarS, and ΔtarMS double mutant cells, were prepared from a laboratory and a community-associated methicillin-resistant S. aureus strain. Here, we describe the unexpected finding that β-GlcNAc WTA-deficient ΔtarS mutant cells (which have intact α-GlcNAc) escape from anti-WTA antibody-mediated opsonophagocytosis, while α-GlcNAc WTA-deficient ΔtarM mutant cells (which have intact β-GlcNAc) are efficiently engulfed by human leukocytes via anti-WTA IgG. Likewise, MBL binding in S. aureus cells was lost in the ΔtarMS double mutant but not in either single mutant. When we determined the serum concentrations of the anti-α- or anti-β-GlcNAc-specific WTA IgGs, anti-β-GlcNAc WTA-IgG was dominant in pooled human IgG fractions and in the intact sera of healthy adults and infants. These data demonstrate the importance of the WTA sugar conformation for human innate and adaptive immunity against S. aureus infection.
    Journal of Biological Chemistry 09/2013; 288(43). DOI:10.1074/jbc.M113.509893 · 4.57 Impact Factor

Publication Stats

8k Citations
784.83 Total Impact Points


  • 1993–2015
    • University of Tuebingen
      • • Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT)
      • • Institute of Medical Microbiology and Hygiene
      • • Institute of Inorganic Chemistry
      Tübingen, Baden-Württemberg, Germany
  • 2014
    • Research Center Borstel
      • Division of Structural Biochemistry
      Borstel, Lower Saxony, Germany
  • 2004–2011
    • Universitätsklinikum Tübingen
      Tübingen, Baden-Württemberg, Germany
  • 2009
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2006
    • University of Iowa
      Iowa City, Iowa, United States