<scp>d</scp>
            -Alanylation of Teichoic Acids Promotes Group A
            <i>Streptococcus</i>
            Antimicrobial Peptide Resistance, Neutrophil Survival, and Epithelial Cell Invasion

Kristian, Sascha A.; Datta, Vivekanand; Weidenmaier, Christopher; Kansal, Rita G.; Fedtke, Iris; Peschel, Andreas; Gallo, Richard L.; Nizet, Victor

doi:10.1128/jb.187.19.6719-6725.2005

Cited by 223 publications

(245 citation statements)

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“…Gene deletion strains of S. iniae, S. pyogenes or S. agalactiae with diminished ability to survive in fresh blood show reduced animal virulence (Buchanan et al, 2005;Datta et al, 2005;Liu et al, 2004;Locke et al, 2007a). These results suggest a fitness advantage conferred by the S. iniae pdi gene against immune clearance by cells or soluble components present in the fish blood circulation.…”

Section: Discussionmentioning

confidence: 58%

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The novel polysaccharide deacetylase homologue Pdi contributes to virulence of the aquatic pathogen Streptococcus iniae

et al. 2010

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The aquatic zoonotic pathogen Streptococcus iniae represents a threat to the worldwide aquaculture industry and poses a risk to humans who handle raw fish. Because little is known about the mechanisms of S. iniae pathogenesis or virulence factors, we established a highthroughput system combining whole-genome pyrosequencing and transposon mutagenesis that allowed us to identify virulence proteins, including Pdi, the polysaccharide deacetylase of S. iniae, that we describe here. Using bioinformatics tools, we identified a highly conserved signature motif in Pdi that is also conserved in the peptidoglycan deacetylase PgdA protein family. A Dpdi mutant was attenuated for virulence in the hybrid striped bass model and for survival in whole fish blood. Moreover, Pdi was found to promote bacterial resistance to lysozyme killing and the ability to adhere to and invade epithelial cells. On the other hand, there was no difference in the autolytic potential, resistance to oxidative killing or resistance to cationic antimicrobial peptides between S. iniae wild-type and Dpdi. In conclusion, we have demonstrated that pdi is involved in S. iniae adherence and invasion, lysozyme resistance and survival in fish blood, and have shown that pdi plays a role in the pathogenesis of S. iniae. Identification of Pdi and other S. iniae virulence proteins is a necessary initial step towards the development of appropriate preventive and therapeutic measures against diseases and economic losses caused by this pathogen. INTRODUCTIONIn the past few decades, the pathogen Streptococcus iniae has emerged as a major hindrance to aquaculture operations worldwide (Agnew & Barnes, 2007), causing economic losses measured in hundreds of millions of dollars annually. In addition, S. iniae has established itself as a zoonotic risk, especially in areas of the world that preferentially prepare and consume raw fish (Lau et al., 2003). To date, at least 25 human cases of invasive streptococcal infection attributed to S. iniae have been confirmed in the USA, Canada, China and Taiwan, many of which were in immunocompromised patients (Agnew & Barnes, 2007;Sun et al., 2007;Weinstein et al., 1997); since there is currently no prospective epidemiological surveillance for human S. iniae infections, the true number may be much higher (Facklam et al., 2005;Lau et al., 2006).In spite of the economic and human health risks that S. iniae presents, a fully assembled genome sequence for this emerging pathogen is not yet available, and very little is known about its disease mechanisms. To better understand the molecular genetic basis of virulence in this versatile pathogen, we created a library of randomly generated transposon mutants that we screened for virulence Abbreviations: AMP, antimicrobial peptide; HSB, hybrid striped bass, i.p., intraperitoneal; PIA, polysaccharide intercellular adhesin, WT, wild-type.3These authors contributed equally to this work.The GenBank/EMBL/DDBJ accession number for the pdi sequence of Streptococcus iniae is FJ664396.Four supplementary f...

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Section: Discussionmentioning

confidence: 58%

“…The incubation temperature was held constant at 30 uC, and the plates were shaken before each reading (every 30 min). Autolysis assays were performed as previously described (Kristian et al, 2005); an EL808 plate reader and Gen5 software were used to monitor decreases in OD.…”

Section: Methodsmentioning

confidence: 99%

The novel polysaccharide deacetylase homologue Pdi contributes to virulence of the aquatic pathogen Streptococcus iniae

et al. 2010

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“…One specific mechanism contributing to GAS AMP resistance is shared with SA -GAS possesses a dltABCD operon that serves to incorporate positively charge residues into its cell wall lipoteichoic acid, leading to electrostatic repulsion of AMPs, thus promoting resistance to cathelicidins and to neutrophil killing [41]. GAS also produces a broad spectrum cysteine protease, SpeB, and the activity of SpeB GAS supernatants has been shown to degrade human cathelicidin LL-37 [42].…”

Section: Group a Streptococcusmentioning

confidence: 99%

Innate barriers against skin infection and associated disorders

Gallo

Nizet

2008

Drug Discovery Today: Disease Mechanisms

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The innate immune system is primarily responsible for prevention of infection of the skin by pathogens, but is also important in control of inflammation. The components of innate immunity are frequently misunderstood based on a historical bias for leukocyte-mediated immune defense. Many participating cell types are often overlooked, in particular epithelial cells that provide an early and critical step to innate immune defense. This review will discuss our epithelial barrier to infection with emphasis on how microbes subvert this system, and human diseases associated with these events.

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“…D-Alanylation confers a positive charge upon LTA and has been demonstrated to have a role in the regulation of autolytic activity (Fischer et al, 1981), the binding of Mg 2+ (Archibald et al, 1973), intragenic coaggregation (Clemans et al, 1999), biofilm formation (Fabretti et al, 2006;Gross et al, 2001), adherence to mammalian cells (Abachin et al, 2002;Weidenmaier et al, 2004), susceptibility to cationic antimicrobial peptides and phagocytic cells (Collins et al, 2002;Henneke et al, 2005;Kristian et al, 2005;Poyart et al, 2003), sensitivity to low pH (Boyd et al, 2000), and modulation of immune stimulation (Chan et al, 2007;Morath et al, 2001). In several bacteria, dlt mutants display an attenuated virulence phenotype in animal models (Abachin et al, 2002;Kristian et al, 2005;Poyart et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…In several bacteria, dlt mutants display an attenuated virulence phenotype in animal models (Abachin et al, 2002;Kristian et al, 2005;Poyart et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Regulation of d-alanylation of lipoteichoic acid in Streptococcus gordonii

et al. 2011

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D-Alanyl esters on lipoteichoic acid (LTA) are involved in adhesion, biofilm formation, resistance to cationic antimicrobial peptides, and immune stimulation. There is evidence that bacteria can modulate the level of D-alanyl esters on LTA in response to challenge, but the mechanism of regulation appears to be different among bacteria. In this study, expression of the dlt operon responsible for D-alanylation of LTA was examined in the commensal bacterium Streptococcus gordonii. dlt expression was assessed using the dlt promoter-lacZ reporter gene assay, LTA D-alanine content measurements and dlt mRNA quantification. The results showed that dlt expression was growth phase-dependent, with the greatest expression at the mid-exponential phase of growth. In contrast to Staphylococcus aureus, dlt expression in Strep. gordonii was not affected by the exogenous addition of Mg 2+ or K + . Interestingly, dlt expression was upregulated under acidic conditions or when cells were stressed with polymyxin B, indicating that cell envelope stress may be a signal for dlt expression. In view of these results, mutants defective in the cell envelope stress LiaSR two-component regulatory system were constructed. The liaS and liaR mutants showed an increase in dlt expression over the parent strain at neutral pH. The mutants failed to respond to low pH and polymyxin B stress; dlt expression remained the same in the presence or absence of these stresses. These results suggest that dlt expression in Strep. gordonii is regulated by the LiaSR regulatory system in response to environmental signals such as pH and polymyxin B. The regulation appears to be complex, involving both repression and activation mechanisms. INTRODUCTIONLipoteichoic acid (LTA) is an amphiphilic polymer of polyphosphoglycerol or polyphosphoribitol anchored to the cytoplasmic membrane by a glycolipid. Each phosphoglycerol or phosphoribitol on this molecule may be modified by glycosylation or, more often, substituted with D-alanyl esters (Fischer, 1988;Fischer et al., 1990). The dlt operon is responsible for the D-alanylation of LTA (Neuhaus & Baddiley, 2003). The operon consists of four genes, dltA, dltB, dltC and dltD. The dltA gene encodes the D-alanyl carrier protein ligase (Dcl), which activates the D-alanine and ligates it to the D-alanyl carrier protein (Dcp). The function of the protein encoded by dltB has not been experimentally established, but it is a transport protein that is thought to serve as a channel to secrete the unfolded D-alanyl Dcp. The dltD gene encodes a membraneassociated protein, which facilitates the binding of Dcp and Dcl for ligation of Dcp with D-alanine. Disruption of any one of the dlt genes will eliminate D-alanylation of LTA.D-Alanylation confers a positive charge upon LTA and has been demonstrated to have a role in the regulation of autolytic activity (Fischer et al., 1981), the binding of Mg 2+ (Archibald et al., 1973), intragenic coaggregation (Clemans et al., 1999), biofilm formation (Fabretti et al., 2006;Gross et al., 2001), adhere...

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d -Alanylation of Teichoic Acids Promotes Group A Streptococcus Antimicrobial Peptide Resistance, Neutrophil Survival, and Epithelial Cell Invasion

Cited by 223 publications

References 50 publications

The novel polysaccharide deacetylase homologue Pdi contributes to virulence of the aquatic pathogen Streptococcus iniae

The novel polysaccharide deacetylase homologue Pdi contributes to virulence of the aquatic pathogen Streptococcus iniae

Innate barriers against skin infection and associated disorders

Regulation of d-alanylation of lipoteichoic acid in Streptococcus gordonii

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