Significant contribution of the <i>pgdA</i> gene to the virulence of <i>Streptococcus suis</i>

Fittipaldi, Nahuel; Sekizaki, Tsutomu; Takamatsu, Daisuke; Domínguez-Punaro, María de la Cruz; Harel, Josée; Bui, Nhat Khai; Vollmer, Waldemar; Gottschalk, Marcelo

doi:10.1111/j.1365-2958.2008.06463.x

Cited by 103 publications

(89 citation statements)

References 45 publications

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“…We showed that lysozyme triggers the production of EF1843 and that, in turn, this protein deacetylates GlcNAc residues in peptidoglycan. This mechanism, which allows E. faecalis to sense one of the components of the host innate immune response, is reminiscent of that described for Streptococcus suis (18). In S. suis, peptidoglycan de-N-acetylation is extremely low when the cells are grown in rich medium.…”

Section: Discussionmentioning

confidence: 81%

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The Lysozyme-Induced Peptidoglycan N -Acetylglucosamine Deacetylase PgdA (EF1843) Is Required for Enterococcus faecalis Virulence

et al. 2012

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f Lysozyme is a key component of the innate immune response in humans that provides a first line of defense against microbes. The bactericidal effect of lysozyme relies both on the cell wall lytic activity of this enzyme and on a cationic antimicrobial peptide activity that leads to membrane permeabilization. Among Gram-positive bacteria, the opportunistic pathogen Enterococcus faecalis has been shown to be extremely resistant to lysozyme. This unusual resistance is explained partly by peptidoglycan Oacetylation, which inhibits the enzymatic activity of lysozyme, and partly by D-alanylation of teichoic acids, which is likely to inhibit binding of lysozyme to the bacterial cell wall. Surprisingly, combined mutations abolishing both peptidoglycan O-acetylation and teichoic acid alanylation are not sufficient to confer lysozyme susceptibility. In this work, we identify another mechanism involved in E. faecalis lysozyme resistance. We show that exposure to lysozyme triggers the expression of EF1843, a protein that is not detected under normal growth conditions. Analysis of peptidoglycan structure from strains with EF1843 loss-and gain-of-function mutations, together with in vitro assays using recombinant protein, showed that EF1843 is a peptidoglycan N-acetylglucosamine deacetylase. EF1843-mediated peptidoglycan deacetylation was shown to contribute to lysozyme resistance by inhibiting both lysozyme enzymatic activity and, to a lesser extent, lysozyme cationic antimicrobial activity. Finally, EF1843 mutation was shown to reduce the ability of E. faecalis to cause lethality in the Galleria mellonella infection model. Taken together, our results reveal that peptidoglycan deacetylation is a component of the arsenal that enables E. faecalis to thrive inside mammalian hosts, as both a commensal and a pathogen.

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Section: Discussionmentioning

confidence: 81%

“…In S. suis, peptidoglycan de-N-acetylation is extremely low when the cells are grown in rich medium. Although the host signal(s) inducing peptidoglycan de-N-acetylation has not been identified, the expression of S. suis deacetylase is strongly stimulated in vivo (18).…”

Section: Discussionmentioning

confidence: 99%

The Lysozyme-Induced Peptidoglycan N -Acetylglucosamine Deacetylase PgdA (EF1843) Is Required for Enterococcus faecalis Virulence

et al. 2012

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“…Bacterial aconitases are subject to oxidation and Fe/S cluster loss, but the apo-form can still play regulatory roles (16,18). PgdA has been shown to be upregulated in response to oxidative stress and upon contact with neutrophils (10,28). Failure of the acnB strain to upregulate PgdA expression under 12% O 2 conditions is in contrast to the wild type, and it led us to hypothesize aconitase was playing a role in deacetylase regulation (Fig.…”

Section: Discussionmentioning

confidence: 99%

Aconitase-Mediated Posttranscriptional Regulation of Helicobacter pylori Peptidoglycan Deacetylase

Austin

Maier

2013

Journal of Bacteriology

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Some bacterial aconitases are bifunctional proteins that function in the citric acid cycle and act as posttranscriptional regulators in response to iron levels and oxidative stress. We explore the role of aconitase (AcnB) in Helicobacter pylori as a posttranscriptional regulator of the cell wall-modifying enzyme peptidoglycan deacetylase, PgdA. Under oxidative stress, PgdA is highly expressed and confers resistance to lysozyme in wild-type cells. PgdA protein expression as well as transcript abundance is significantly decreased in an acnB mutant. In the wild type, pgdA mRNA half-life was 13 min, whereas the half-life for the acnB strain was 7 min. Based on electrophoretic mobility shift assays and RNA footprinting, the H. pylori apo-AcnB binds to the 3=-untranslated region of the pgdA RNA transcript. Some of the protected bases (from footprinting) were localized in proposed stem-loop structures. AcnB-pgdA transcript binding was abolished by the addition of iron. The acnB strain is more susceptible to lysozyme-mediated killing and was attenuated in its ability to colonize mice. The results support a model whereby apo-AcnB directly interacts with the pgdA transcript to enhance stability and increase deacetylase enzyme expression, which impacts in vivo survival.

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“…S5A in the supplemental material). We next reasoned that the major bactericidal factor could be macrophages, neutrophils, or serum, since all have been previously implicated in the killing of lysozyme-sensitive bacteria (9,50,51). Upon the infection of bone marrow-derived macrophages, only a small defect was observed when the pgdA oatA pbpX triple mutant, the most lysozyme-sensitive strain, was used (see Fig.…”

Section: Resultsmentioning

confidence: 99%

Listeria monocytogenes Is Resistant to Lysozyme through the Regulation, Not the Acquisition, of Cell Wall-Modifying Enzymes

et al. 2014

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Listeria monocytogenes is a Gram-positive facultative intracellular pathogen that is highly resistant to lysozyme, a ubiquitous enzyme of the innate immune system that degrades cell wall peptidoglycan. Two peptidoglycan-modifying enzymes, PgdA and OatA, confer lysozyme resistance on L. monocytogenes; however, these enzymes are also conserved among lysozyme-sensitive nonpathogens. We sought to identify additional factors responsible for lysozyme resistance in L. monocytogenes. A forward genetic screen for lysozyme-sensitive mutants led to the identification of 174 transposon insertion mutations that mapped to 13 individual genes. Four mutants were killed exclusively by lysozyme and not other cell wall-targeting molecules, including the peptidoglycan deacetylase encoded by pgdA, the putative carboxypeptidase encoded by pbpX, the orphan response regulator encoded by degU, and the highly abundant noncoding RNA encoded by rli31. Both degU and rli31 mutants had reduced expression of pbpX and pgdA, yet DegU and Rli31 did not regulate each other. Since pbpX and pgdA are also present in lysozyme-sensitive bacteria, this suggested that the acquisition of novel enzymes was not responsible for lysozyme resistance, but rather, the regulation of conserved enzymes by DegU and Rli31 conferred high lysozyme resistance. Each lysozyme-sensitive mutant exhibited attenuated virulence in mice, and a time course of infection revealed that the most lysozyme-sensitive strain was killed within 30 min of intravenous infection, a phenotype that was recapitulated in purified blood. Collectively, these data indicate that the genes required for lysozyme resistance are highly upregulated determinants of L. monocytogenes pathogenesis that are required for avoiding the enzymatic activity of lysozyme in the blood. Lysozyme is a ubiquitous bactericidal enzyme found in the blood, bodily secretions, and phagocytic cells of all animals (1-3). Lysozyme degrades the bacterial cell wall by hydrolyzing the ␤1-4 linkage between the N-acetylglucosamine (NAG) and Nacetylmuramic acid (NAM) residues that comprise the peptidoglycan backbone, often resulting in bacteriolysis (4). Not surprisingly, many pathogens have evolved mechanisms of lysozyme resistance (5, 6). The best-characterized mechanisms of lysozyme resistance involve the acetylation state of the peptidoglycan, catalyzed by the deacetylase PgdA and/or the acetyltransferase OatA. PgdA deacetylates the amino group of NAG, while OatA O-acetylates NAM, converting the sugar backbone into a poor lysozyme substrate (7,8). pgdA mutants of Streptococcus pneumoniae and oatA mutants of Staphylococcus aureus are lysozyme sensitive, and in each case, lysozyme-sensitive mutants are attenuated in animal models of infection (7-10).Listeria monocytogenes is a facultative intracellular pathogen of animals and humans that causes severe disease in pregnant women and immunocompromised individuals (11). Both PgdA and OatA contribute to lysozyme resistance in L. monocytogenes, and pgdA mutants are attenuated during oral a...

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Significant contribution of the pgdA gene to the virulence of Streptococcus suis

Cited by 103 publications

References 45 publications

The Lysozyme-Induced Peptidoglycan N -Acetylglucosamine Deacetylase PgdA (EF1843) Is Required for Enterococcus faecalis Virulence

The Lysozyme-Induced Peptidoglycan N -Acetylglucosamine Deacetylase PgdA (EF1843) Is Required for Enterococcus faecalis Virulence

Aconitase-Mediated Posttranscriptional Regulation of Helicobacter pylori Peptidoglycan Deacetylase

Listeria monocytogenes Is Resistant to Lysozyme through the Regulation, Not the Acquisition, of Cell Wall-Modifying Enzymes

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