scholarly journals The impact of Staphylococcus aureus cell wall glycosylation on langerin recognition and Langerhans cell activation

2020 ◽  
Author(s):  
A Hendriks ◽  
R van Dalen ◽  
S Ali ◽  
D Gerlach ◽  
GA van der Marel ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Cell Activation ◽  
Teichoic Acid ◽  
Binding Studies ◽  
Wall Teichoic Acid ◽  
Linkage Position ◽  
Antigen Presenting ◽  
The Impact

AbstractStaphylococcus aureus is the leading cause of skin and soft tissue infections. It remains incompletely understood how skin-resident immune cells respond to S. aureus invasion and contribute to an effective immune response. Langerhans cells (LCs), the only professional antigen-presenting cell type in the epidermis, sense S. aureus through their pattern-recognition receptor langerin, triggering a pro-inflammatory response. Langerin specifically recognizes the β-1,4-linked N-acetylglucosamine (β-GlcNAc) modification, which requires the glycosyltransferase TarS, on the cell wall glycopolymer Wall Teichoic Acid (WTA). Recently, an alternative WTA glycosyltransferase, TarP, was identified in methicillin-resistant S. aureus strains belonging to clonal complexes (CC) 5 and CC398. TarP also modifies WTA with β-GlcNAc but at the C-3 position of the WTA ribitol phosphate (RboP) subunit. Here, we aimed to unravel the impact of β-GlcNAc linkage position for langerin binding and LC activation. In addition, we performed structure-binding studies using a small panel of unique chemically-synthesized WTA molecules to assess langerin-WTA binding requirements. Using FITC-labeled recombinant human langerin and genetically-modified S. aureus strains, we observed that langerin similarly recognized bacteria that produce either TarS- or TarP-modified WTA. Furthermore, using chemically-synthesized WTA, representative of the different S. aureus WTA glycosylation patterns, established that β-GlcNAc is sufficient to confer langerin binding. Functionally, tarP-expressing S. aureus induce increased cytokine production and maturation of in vitro-generated LCs compared to tarSexpressing S. aureus. Overall, our data suggest that LCs are able to sense all β-GlcNAc-WTA producing S. aureus strains, likely performing an important role as first responders upon S. aureus skin invasion.

scholarly journals YycH and YycI Regulate Expression of Staphylococcus aureus Autolysins by Activation of WalRK Phosphorylation

2020 ◽  
Vol 8 (6) ◽  
pp. 870
Author(s):  
Mike Gajdiss ◽  
Ian R. Monk ◽  
Ute Bertsche ◽  
Janina Kienemund ◽  
Tanja Funk ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Teichoic Acid ◽  
Regulatory System ◽  
Regulatory Function ◽  
Wall Teichoic Acid ◽  
Dependent Cell ◽  
Severe Infections

Staphylococcus aureus is a facultative pathogen that can encode numerous antibiotic resistance and immune evasion genes and can cause severe infections. Reduced susceptibility to last resort antibiotics such as vancomycin and daptomycin is often associated with mutations in walRK, an essential two-component regulatory system (TCS). This study focuses on the WalK accessory membrane proteins YycH and YycI and their influence on WalRK phosphorylation. Depletion of YycH and YycI by antisense RNA caused an impaired autolysis, indicating a positive regulatory function on WalK as has been previously described. Phosphorylation assays with full-length recombinant proteins in phospholipid liposomes showed that YycH and YycI stimulate WalK activity and that both regulatory proteins are needed for full activation of the WalK kinase. This was validated in vivo through examining the phosphorylation status of WalR using Phos-tag SDS-PAGE with a yycHI deletion mutant exhibiting reduced levels of phosphorylated WalR. In the yycHI knockdown strain, muropeptide composition of the cell wall was not affected, however, the wall teichoic acid content was increased. In conclusion, a direct modulation of WalRK phosphorylation activity by the accessory proteins YycH and YycI is reported both in vitro and in vivo. Taken together, our results show that YycH and YycI are important in the direct regulation of WalRK-dependent cell wall metabolism.

scholarly journals An Antibiotic That Inhibits a Late Step in Wall Teichoic Acid Biosynthesis Induces the Cell Wall Stress Stimulon in Staphylococcus aureus

2012 ◽  
Vol 56 (4) ◽  
pp. 1810-1820 ◽  
Author(s):  
Jennifer Campbell ◽  
Atul K. Singh ◽  
Jonathan G. Swoboda ◽  
Michael S. Gilmore ◽  
Brian J. Wilkinson ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Osmotic Stress ◽  
Late Stage ◽  
Teichoic Acid ◽  
Wall Stress ◽  
Wall Teichoic Acid ◽  
Content Type ◽  
Cell Wall Stress

ABSTRACTWall teichoic acids (WTAs) are phosphate-rich, sugar-based polymers attached to the cell walls of most Gram-positive bacteria. InStaphylococcus aureus, these anionic polymers regulate cell division, protect cells from osmotic stress, mediate host colonization, and mask enzymatically susceptible peptidoglycan bonds. Although WTAs are not required for survivalin vitro, blocking the pathway at a late stage of synthesis is lethal. We recently discovered a novel antibiotic, targocil, that inhibits a late acting step in the WTA pathway. Its target is TarG, the transmembrane component of the ABC transporter (TarGH) that exports WTAs to the cell surface. We examined here the effects of targocil onS. aureususing transmission electron microscopy and gene expression profiling. We report that targocil treatment leads to multicellular clusters containing swollen cells displaying evidence of osmotic stress, strongly induces the cell wall stress stimulon, and reduces the expression of key virulence genes, includingdltABCDand capsule genes. We conclude that WTA inhibitors that act at a late stage of the biosynthetic pathway may be useful as antibiotics, and we present evidence that they could be particularly useful in combination with beta-lactams.

scholarly journals Duplication of Teichoic Acid Biosynthetic Genes in Staphylococcus aureus Leads to Functionally Redundant Poly(Ribitol Phosphate) Polymerases

2008 ◽  
Vol 190 (16) ◽  
pp. 5642-5649 ◽  
Author(s):  
Mark P. Pereira ◽  
Michael A. D'Elia ◽  
Justyna Troczynska ◽  
Eric D. Brown
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Teichoic Acid ◽  
Gene Clusters ◽  
Opportunistic Pathogen ◽  
Null Mutant ◽  
Wall Teichoic Acid ◽  
Rate Limiting Step ◽  
Wall Teichoic Acids

ABSTRACT Wall teichoic acids are anionic phosphate-rich polymers that are part of the complex meshwork of carbohydrates that make up the gram-positive cell wall. These polymers are essential to the proper rod-shaped morphology of Bacillus subtilis and have been shown to be an important virulence determinant in the nosocomial opportunistic pathogen Staphylococcus aureus. Together, sequence-based studies, in vitro experiments with biosynthetic proteins, and analyses of the chemical structure of wall teichoic acid have begun to shed considerable light on our understanding of the biogenesis of this polymer. Nevertheless, some paradoxes remain unresolved. One of these involves a putative duplication of genes linked to CDP-ribitol synthesis (tarI′J′ and tarIJ) as well as poly(ribitol phosphate) polymerization (tarK and tarL) in S. aureus. In the work reported here, we performed careful studies of the dispensability of each gene and discovered a functional redundancy in the duplicated gene clusters. We were able to create mutants in either of the putative ribitol phosphate polymerases (encoded by tarK and tarL) without affecting teichoic acid levels in the S. aureus cell wall. Although genes linked to CDP-ribitol synthesis are also duplicated, a null mutant in only one of these (tarI′J′) could be obtained, while tarIJ remained essential. Suppression analysis of the tarIJ null mutant indicated that the mechanism of dysfunction in tarI′J′ is due to poor translation of the TarJ′ enzyme, which catalyzes the rate-limiting step in CDP-ribitol formation. This work provides new insights into understanding the complex synthetic steps of the ribitol phosphate polymer in S. aureus and has implications on specifically targeting enzymes involved in polymer biosynthesis for antimicrobial design.

scholarly journals Glycosylation of Staphylococcus aureus cell wall teichoic acid is influenced by environmental conditions

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Noëlle Mistretta ◽  
Marina Brossaud ◽  
Fabienne Telles ◽  
Violette Sanchez ◽  
Philippe Talaga ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Environmental Conditions ◽  
Teichoic Acid ◽  
Wall Teichoic Acid

scholarly journals Impact of Glycan Linkage to Staphylococcus aureus Wall Teichoic Acid on Langerin Recognition and Langerhans Cell Activation

2021 ◽  
Vol 7 (3) ◽  
pp. 624-635
Author(s):  
Astrid Hendriks ◽  
Rob van Dalen ◽  
Sara Ali ◽  
David Gerlach ◽  
Gijsbert A. van der Marel ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Activation ◽  
Teichoic Acid ◽  
Langerhans Cell ◽  
Wall Teichoic Acid

scholarly journals LcpB Is a Pyrophosphatase Responsible for Wall Teichoic Acid Synthesis and Virulence in Staphylococcus aureus Clinical Isolate ST59

2021 ◽  
Vol 12 ◽  
Author(s):  
Ting Pan ◽  
Jing Guan ◽  
Yujie Li ◽  
Baolin Sun
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Molecular Mechanisms ◽  
Teichoic Acid ◽  
Acid Synthesis ◽  
Cell Wall Synthesis ◽  
Wall Teichoic Acid ◽  
Independent Manner ◽  
Methicillin Resistant

The community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) causes severe pandemics primarily consisting of skin and soft tissue infections. However, the underlying pathomechanisms of the bacterium are yet to fully understood. The present study identifies LcpB protein, which belongs to the LytR-A-Psr (LCP) family, is crucial for cell wall synthesis and virulence in S. aureus. The findings revealed that LcpB is a pyrophosphatase responsible for wall teichoic acid synthesis. The results also showed that LcpB regulates enzyme activity through specific key arginine sites in its LCP domain. Furthermore, knockout of lcpB in the CA-MRSA isolate ST59 resulted in enhanced hemolytic activity, enlarged of abscesses, and increased leukocyte infiltration. Meanwhile, we also found that LcpB regulates virulence in agr-independent manner and the key sites for pyrophosphatase of LcpB play critical roles in regulating the virulence. In addition, the results showed that the role of LcpB was different between methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA). This study therefore highlights the dual role of LcpB in cell wall synthesis and regulation of virulence. These insights on the underlying molecular mechanisms can thus guide the development of novel anti-infective strategies.

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