D-Alanylation of Lipoteichoic Acids Confers Resistance to Cationic Peptides in Group B Streptococcus by Increasing the Cell Wall Density
| Autor: | Arkadi Bitler, Ron Saar-Dover, Arnaud Firon, Liraz Shmuel-Galia, Patrick Trieu-Cuot, Ravit Nezer, Yechiel Shai, Eyal Shimoni |
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| Přispěvatelé: | Department of Biological Chemistry, Weizmann Institute, Chemical Research Support [Rehovot], Weizmann Institute of Science [Rehovot, Israël], Biologie des Bactéries pathogènes à Gram-positif, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Electron Microscopy Unit, This work was supported by fundings from Pasteur-Weizmann (WIS Project Number 720047 to PTC and YS), Israel Ministry of Health, Grant No. 7291 (to YS), and by the National Institutes of Health (NIH) Grant R01 AI052455-06A (to PTC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Lipopolysaccharides
Cell Peptide Microscopy Atomic Force Biochemistry chemistry.chemical_compound Cell Wall lcsh:QH301-705.5 Peptide sequence chemistry.chemical_classification 0303 health sciences Teichoic acid Alanine biology Streptococci Drug Resistance Microbial Bacterial Pathogens Anti-Bacterial Agents medicine.anatomical_structure Research Article lcsh:Immunologic diseases. Allergy Surface Properties Gram-positive bacteria Molecular Sequence Data Immunology Biophysics Microbial Sensitivity Tests Microbiology Cell wall 03 medical and health sciences Microscopy Electron Transmission Streptococcal Infections Virology Defense Proteins Genetics medicine Humans Amino Acid Sequence Biology Molecular Biology 030304 developmental biology Gram Positive Innate immune system 030306 microbiology Osmolar Concentration Proteins Streptococcus biology.organism_classification [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology Teichoic Acids lcsh:Biology (General) chemistry Parasitology lcsh:RC581-607 Protein Processing Post-Translational Bacteria Antimicrobial Cationic Peptides |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Public Library of Science, 2012, 8 (9), pp.e1002891. ⟨10.1371/journal.ppat.1002891⟩ PLoS Pathogens, 2012, 8 (9), pp.e1002891. ⟨10.1371/journal.ppat.1002891⟩ PLoS Pathogens, Vol 8, Iss 9, p e1002891 (2012) |
| ISSN: | 1553-7366 1553-7374 |
| DOI: | 10.1371/journal.ppat.1002891⟩ |
| Popis: | Cationic antimicrobial peptides (CAMPs) serve as the first line of defense of the innate immune system against invading microbial pathogens. Gram-positive bacteria can resist CAMPs by modifying their anionic teichoic acids (TAs) with D-alanine, but the exact mechanism of resistance is not fully understood. Here, we utilized various functional and biophysical approaches to investigate the interactions of the human pathogen Group B Streptococcus (GBS) with a series of CAMPs having different properties. The data reveal that: (i) D-alanylation of lipoteichoic acids (LTAs) enhance GBS resistance only to a subset of CAMPs and there is a direct correlation between resistance and CAMPs length and charge density; (ii) resistance due to reduced anionic charge of LTAs is not attributed to decreased amounts of bound peptides to the bacteria; and (iii) D-alanylation most probably alters the conformation of LTAs which results in increasing the cell wall density, as seen by Transmission Electron Microscopy, and reduces the penetration of CAMPs through the cell wall. Furthermore, Atomic Force Microscopy reveals increased surface rigidity of the cell wall of the wild-type GBS strain to more than 20-fold that of the dltA mutant. We propose that D-alanylation of LTAs confers protection against linear CAMPs mainly by decreasing the flexibility and permeability of the cell wall, rather than by reducing the electrostatic interactions of the peptide with the cell surface. Overall, our findings uncover an important protective role of the cell wall against CAMPs and extend our understanding of mechanisms of bacterial resistance. Author Summary Cationic antimicrobial peptides (CAMPs) represent important evolutionarily conserved elements of innate immunity and their killing mechanism involves bacterial cell wall permeation. As a result, gram-positive bacteria can resist CAMPs by modifying their anionic teichoic acids (TAs) following incorporation of D-alanyl residues to neutralize their surface charge, a reaction catalyzed by the dlt operon gene product. Here, we demonstrate that this electrochemical modification changes the barrier properties of Group B Streptococcus cell wall and inactivation of the dlt operon activity results in CAMP sensitivity. However, despite the major increase in the surface charge of the mutant, no increased electrostatic binding of CAMPs is observed. Rather, D-alanine incorporation protects the bacterial membrane by reducing the penetration of CAMPs through the cell wall. Accordingly, a dlt mutant was more susceptible to perforation by CAMPs and its cell wall nanostructure was significantly altered. Overall, we demonstrate a novel protective role of the cell wall against CAMPs which should enable bacterial invaders to survive upon host's colonization. |
| Databáze: | OpenAIRE |
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