Staphylococcus aureus Targets the Duffy Antigen Receptor for Chemokines (DARC) to Lyse Erythrocytes

Spaan, András N.; Reyes‐Robles, Tamara; Badiou, Cédric; Cochet, Sylvie; Boguslawski, Kristina M.; Yoong, Pauline; Day, Christopher J.; Haas, Carla J C Gosselaar-de; Kessel, Kok P. M. van; Vandenesch, François; Jennings, Michael P.; Kim, Caroline Le Van; Colin, Yves; Strijp, Jos A. G. van; Henry, Thomas; Torres, Victor J.

doi:10.1016/j.chom.2015.08.001

Cited by 98 publications

(147 citation statements)

References 47 publications

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“…8C). Lysis of human red blood cells by S. aureus can be mediated by a number of different hemolytic toxins (38); therefore, the data in Fig. 8 strongly suggest that one or more of these factors require PpiB for optimal activity.…”

Section: Discussionmentioning

confidence: 93%

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An Intracellular Peptidyl-Prolyl cis / trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease

et al. 2017

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Staphylococcus aureus is an important human pathogen that relies on a large repertoire of secreted and cell wall-associated proteins for pathogenesis. Consequently, the ability of the organism to cause disease is absolutely dependent on its ability to synthesize and successfully secrete these proteins. In this study, we investigate the role of peptidyl-prolyl cis/trans isomerases (PPIases) on the activity of the S. aureus secreted virulence factor nuclease (Nuc). We identify a staphylococcal cyclophilin-type PPIase (PpiB) that is required for optimal activity of Nuc. Disruption of ppiB results in decreased nuclease activity in culture supernatants; however, the levels of Nuc protein are not altered, suggesting that the decrease in activity results from misfolding of Nuc in the absence of PpiB. We go on to demonstrate that PpiB exhibits PPIase activity in vitro, is localized to the bacterial cytosol, and directly interacts with Nuc in vitro to accelerate the rate of Nuc refolding. Finally, we demonstrate an additional role for PpiB in S. aureus hemolysis and demonstrate that the S. aureus parvulin-type PPIase PrsA also plays a role in the activity of secreted virulence factors. The deletion of prsA leads to a decrease in secreted protease and phospholipase activity, similar to that observed in other Gram-positive pathogens. Together, these results demonstrate, for the first time to our knowledge, that PPIases play an important role in the secretion of virulence factors in S. aureus.IMPORTANCE Staphylococcus aureus is a highly dangerous bacterial pathogen capable of causing a variety of infections throughout the human body. The ability of S. aureus to cause disease is largely due to an extensive repertoire of secreted and cell wall-associated proteins, including adhesins, toxins, exoenzymes, and superantigens. These virulence factors, once produced, are typically transported across the cell membrane by the secretory (Sec) system in a denatured state. Consequently, once outside the cell, they must refold into their active form. This step often requires the assistance of bacterial folding proteins, such as PPIases. In this work, we investigate the role of PPIases in S. aureus and uncover a cyclophilin-type enzyme that assists in the folding/refolding of staphylococcal nuclease.KEYWORDS cyclophilin, Nuc, PI-PLC, PPIase, parvulin, PpiB, PrsA, Staphylococcus aureus, nuclease, protease T he proline peptide bond is unique in nature in that both the cis and trans forms can occur in vivo, with the cis conformation existing approximately 6.5% of the time (1). In contrast, for all other naturally occurring amino acids, steric hindrance between side chains precludes the cis form and overwhelmingly favors the trans form (2). The presence of both the cis and trans forms of proline peptide bonds has important consequences for protein tertiary structure. In certain cases, the isomerization state of

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Section: Discussionmentioning

confidence: 93%

“…aureus produces a number of toxins capable of lysing human red blood cells (38). To determine if PPIases affect the activity of these toxins, an erythrocyte lysis assay was performed using culture supernatants from wild-type and prsA, ppiB, and tig mutant strains.…”

Section: Role Of S Aureus Ppiases In Nuclease Activitymentioning

confidence: 99%

An Intracellular Peptidyl-Prolyl cis / trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease

et al. 2017

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“…The possibility also exists that some Duffy-null individuals may express a low level of Duffy blood group antigen on their erythrocytes despite the inability of GATA1 to bind to the Duffy blood group locus. Three studies have failed to find Duffy blood group antigen on the surface of Duffy-null erythrocytes (14,37,38), although extremely low copy number may have been missed. The possibility of low expression of Duffy in P. vivax-infected Duffy-null individuals has not yet been excluded.…”

Section: Discussionmentioning

confidence: 99%

Role of Plasmodium vivax Duffy-binding protein 1 in invasion of Duffy-null Africans

Gunalan

Hostetler

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

121

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The ability of the malaria parasite Plasmodium vivax to invade erythrocytes is dependent on the expression of the Duffy blood group antigen on erythrocytes. Consequently, Africans who are null for the Duffy antigen are not susceptible to P. vivax infections. Recently, P. vivax infections in Duffy-null Africans have been documented, raising the possibility that P. vivax, a virulent pathogen in other parts of the world, may expand malarial disease in Africa. P. vivax binds the Duffy blood group antigen through its Duffy-binding protein 1 (DBP1). To determine if mutations in DBP1 resulted in the ability of P. vivax to bind Duffy-null erythrocytes, we analyzed P. vivax parasites obtained from two Duffy-null individuals living in Ethiopia where Duffy-null and -positive Africans live side-by-side. We determined that, although the DBP1s from these parasites contained unique sequences, they failed to bind Duffy-null erythrocytes, indicating that mutations in DBP1 did not account for the ability of P. vivax to infect Duffy-null Africans. However, an unusual DNA expansion of DBP1 (three and eight copies) in the two Duffy-null P. vivax infections suggests that an expansion of DBP1 may have been selected to allow low-affinity binding to another receptor on Duffy-null erythrocytes. Indeed, we show that Salvador (Sal) I P. vivax infects Squirrel monkeys independently of DBP1 binding to Squirrel monkey erythrocytes. We conclude that P. vivax Sal I and perhaps P. vivax in Duffy-null patients may have adapted to use new ligand-receptor pairs for invasion.Plasmodium vivax | Duffy blood group antigen | Duffy-binding protein | DNA expansionI n 1975 we identified the failure of Plasmodium knowlesi to invade Duffy-null erythrocytes (1). We assumed that the Duffy blood group null phenotype, a common African phenotype, conferred resistance in Africans to P. vivax, a Plasmodium closely related to P. knowlesi. Subsequent studies demonstrated that African American volunteers who were Duffy-null were resistant to mosquito-transmitted P. vivax (2). In addition, African American soldiers in Vietnam who were infected with P. vivax were all Duffypositive (3). Furthermore, African Americans in a village in Honduras who were infected with P. vivax were all Duffy-positive whereas those infected with P. falciparum were both Duffy-null and -positive (4). We concluded that Duffy null was the basis of resistance to P. vivax by Africans.The molecular basis of Duffy null was a single point mutation in the GATA1-binding sequence in the promotor region 5′ to the Duffy blood group ORF (Fig. 1B) that led to Duffy-blood-groupnull erythrocytes (5). In vitro studies with P. knowlesi demonstrated that the invasive merozoites were able to bind and reorient apically with Duffy-null erythrocytes but could not form a junction as occurred in Duffy-positive erythrocytes, indicating that the Duffy blood group was required for P. vivax invasion (6). Later, in P. knowlesi parasite culture supernatants, the parasite ligand binding to Duffy blood group antigen was identi...

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“…The success of S. aureus can be attributed its broad array of host-targeting virulence factors, most notably its arsenal of seven different β-barrel PFTs: α-hemolysin (α-toxin, Hla) and six bicomponent leukocidins [4, 7]. Deletion mutants lacking one or more of these PFTs demonstrate attenuation in various models of infection and intoxication relative to their isogenic wildtype counterparts [8–15]. However, it is still unclear whether these different PFTs exhibit coordinated activity in the context of human infection to amplify the virulence of the pathogen.…”

Section: Introductionmentioning

confidence: 99%

Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity

Seilie

Wardenburg

2017

Seminars in Cell & Developmental Biology

173

136

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Staphylococcus aureus is a prominent human pathogen capable of infecting a variety of host species and tissue sites. This versatility stems from the pathogen’s ability to secrete diverse host-damaging virulence factors. Among these factors, the S. aureus pore-forming toxins (PFTs), α-toxin and the bicomponent leukocidins, have garnered much attention for their ability to lyse cells at low concentrations and modulate disease severity. Although many of these toxins were discovered nearly a century ago, their host cell specificity has only been elucidated over the past five to six years, starting with the discovery of the eukaryotic receptor for α-toxin and rapidly followed by identification of the leukocidin receptors. The identification of these receptors has revealed the species- and cell type-specificity of toxin binding, and provided insight into non-lytic effects of PFT intoxication that contribute to disease pathogenesis.

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Staphylococcus aureus Targets the Duffy Antigen Receptor for Chemokines (DARC) to Lyse Erythrocytes

Cited by 98 publications

References 47 publications

An Intracellular Peptidyl-Prolyl cis / trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease

An Intracellular Peptidyl-Prolyl cis / trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease

Role of Plasmodium vivax Duffy-binding protein 1 in invasion of Duffy-null Africans

Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity

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