Staphylococcus pseudintermedius Surface Protein L (SpsL) Is Required for Abscess Formation in a Murine Model of Cutaneous Infection

Richards, Amy C.; O’Shea, Marie; Beard, Philippa M.; Goncheva, Mariya I.; Tuffs, Stephen W.; Fitzgerald, J. Ross; Lengeling, Andreas

doi:10.1128/iai.00631-18

Cited by 14 publications

(13 citation statements)

References 46 publications

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“…The exact functions of only some of these S. pseudintermedius surface proteins (Sps) have been deciphered to date. SpsD, SpsL, and SpsO have been shown to participate in bacterial attachment to the host extracellular matrix and, thus, are involved in the pathogenesis of S. pseudintermedius (32)(33)(34). Similarly, spsQ, which is analogous to the S. aureus staphylococcal protein A (SpA) gene (spa), has been reported to be an important virulence determinant in S. pseudintermedius (21,31).…”

Section: Resultsmentioning

confidence: 99%

Staphylococcal Protein A ( spa ) Locus Is a Hot Spot for Recombination and Horizontal Gene Transfer in Staphylococcus pseudintermedius

Zukancic

Khan

Gurmen

et al. 2020

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Staphylococcus pseudintermedius is a major canine pathogen but also occasionally colonizes and infects humans. Multidrug-resistant methicillin-resistant S. pseudintermedius (MDR MRSP) strains have emerged globally, making treatment and control of this pathogen challenging. Sequence type 71 (ST71), ST68, and ST45 are the most widespread and successful MDR MRSP clones. The potential genetic factors underlying the clonal success of these and other predominant clones remain unknown. Characterization of the pangenome, lineage-associated accessory genes, and genes acquired through horizontal gene transfer from other bacteria is important for identifying such factors. Here, we analyzed genome sequence data from 622 S. pseudintermedius isolates to investigate the evolution of pathogenicity across lineages. We show that the predominant clones carry one or more lineage-associated virulence genes. The gene encoding staphylococcal protein A (SpA), a key virulence factor involved in immune evasion and a potential vaccine antigen, is deleted in 62% of isolates. Most importantly, we have discovered that the spa locus is a hot spot for recombination and horizontal gene transfer in S. pseudintermedius, where genes related to restriction modification, prophage immunity, mercury resistance, and nucleotide and carbohydrate metabolism have been acquired in different lineages. Our study also establishes that ST45 is composed of two distinct sublineages that differ in their accessory gene content and virulence potential. Collectively, this study reports several previously undetected lineage-associated genetic factors that may have a role in the clonal success of the major MDR MRSP clones. These data provide a framework for future experimental studies on S. pseudintermedius pathogenesis and for developing novel therapeutics against this pathogen. IMPORTANCE Staphylococcus pseudintermedius is a major canine pathogen but can also occasionally infect humans. Identification of genetic factors contributing to the virulence and clonal success of multidrug-resistant S. pseudintermedius clones is critical for the development of therapeutics against this pathogen. Here, we characterized the genome sequences of a global collection of 622 S. pseudintermedius isolates. We show that all major clones, besides carrying core virulence genes, which are present in all strains, carry one or more lineage-specific genes. Many of these genes have been acquired from other bacterial species through a horizontal gene transfer mechanism. Importantly, we have discovered that the staphylococcal protein A gene (spa), a widely used marker for molecular typing of S. pseudintermedius strains and a potential vaccine candidate antigen, is deleted in 62% of strains. Furthermore, the spa locus in S. pseudintermedius acts as a reservoir to accumulate lineage-associated genes with adaptive functions.

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Section: Resultsmentioning

confidence: 99%

Staphylococcal Protein A ( spa ) Locus Is a Hot Spot for Recombination and Horizontal Gene Transfer in Staphylococcus pseudintermedius

Zukancic

Khan

Gurmen

et al. 2020

mSphere

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“…pseudintermedius are unknown. Previously, we demonstrated that SpsL contributed to abscess formation in a murine model of subcutaneous infection indicating that it is a virulence factor during the pathogenesis of skin infection [22]. The poor binding of SpsL to murine fibrinogen suggests that this effect is not mediated by the interaction of SpsL with murine fibrinogen [22].…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we demonstrated that SpsL contributed to abscess formation in a murine model of subcutaneous infection indicating that it is a virulence factor during the pathogenesis of skin infection [22]. The poor binding of SpsL to murine fibrinogen suggests that this effect is not mediated by the interaction of SpsL with murine fibrinogen [22]. Here we demonstrate that SpsL mediates high strength binding to canine fibrinogen in a host-specific manner and that this host-adaptation conferred the ability to mediate bacterial aggregation and biofilm formation.…”

Section: Discussionmentioning

confidence: 99%

“…While SpsD was encoded by closely-related species of staphylococci associated with non-canine host-species, SpsL was specific for S . pseudintermedius [21] and was shown to be required for abscess formation in a murine skin infection model [22]. Previous sequence and structural analysis of SpsL identified a similar domain architecture to the fibronectin-binding proteins of S .…”

Section: Introductionmentioning

confidence: 99%

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Host-specialized fibrinogen-binding by a bacterial surface protein promotes biofilm formation and innate immune evasion

et al. 2019

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Fibrinogen is an essential part of the blood coagulation cascade and a major component of the extracellular matrix in mammals. The interface between fibrinogen and bacterial pathogens is an important determinant of the outcome of infection. Here, we demonstrate that a canine host-restricted skin pathogen, Staphylococcus pseudintermedius , produces a cell wall-associated protein (SpsL) that has evolved the capacity for high strength binding to canine fibrinogen, with reduced binding to fibrinogen of other mammalian species including humans. Binding occurs via the surface-expressed N2N3 subdomains, of the SpsL A-domain, to multiple sites in the fibrinogen α-chain C-domain by a mechanism analogous to the classical dock, lock, and latch binding model. Host-specific binding is dependent on a tandem repeat region of the fibrinogen α-chain, a region highly divergent between mammals. Of note, we discovered that the tandem repeat region is also polymorphic in different canine breeds suggesting a potential influence on canine host susceptibility to S . pseudintermedius infection. Importantly, the strong host-specific fibrinogen-binding interaction of SpsL to canine fibrinogen is essential for bacterial aggregation and biofilm formation, and promotes resistance to neutrophil phagocytosis, suggesting a key role for the interaction during pathogenesis. Taken together, we have dissected a bacterial surface protein-ligand interaction resulting from the co-evolution of host and pathogen that promotes host-specific innate immune evasion and may contribute to its host-restricted ecology.

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“…Staphylococcus pseudintermedius , a staphylococcal species responsible of canine otitis, pyoderma and surgical wound infections, expresses two cell wall-anchored proteins, SpsD and SpsL, showing a organization and functionality similar to FnBPA and FnBPB and that are likely to be important in tissue colonization and pathogenesis ( Geoghegan et al, 2009 ; Bannoehr et al, 2012 ; Richards et al, 2018 ). SpsD contains a secretory signal sequence at the N-terminus and a C-terminal LPXTG motif required for anchoring the protein to the wall peptidoglycan.…”

Section: Fnbp-like Proteins From Other Staphylococcal Speciesmentioning

confidence: 99%

The Multivalent Role of Fibronectin-Binding Proteins A and B (FnBPA and FnBPB) of Staphylococcus aureus in Host Infections

Speziale

Pietrocola

2020

Front. Microbiol.

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Staphylococcus aureus, one of the most important human pathogens, is the causative agent of several infectious diseases including sepsis, pneumonia, osteomyelitis, endocarditis and soft tissue infections. This pathogenicity is due to a multitude of virulence factors including several cell wall-anchored proteins (CWA). CWA proteins have modular structures with distinct domains binding different ligands. The majority of S. aureus strains express two CWA fibronectin (Fn)-binding adhesins FnBPA and FnBPB (Fn-binding proteins A and B), which are encoded by closely related genes. The N-terminus of FnBPA and FnBPB comprises an A domain which binds ligands such as fibrinogen, elastin and plasminogen. The A domain of FnBPB also interacts with histones and this binding results in the neutralization of the antimicrobial activity of these molecules. The C-terminal moiety of these adhesins comprises a long, intrinsically disordered domain composed of 11/10 fibronectin-binding repeats. These repetitive motifs of FnBPs promote invasion of cells that are not usually phagocytic via a mechanism by which they interact with integrin α 5 β 1 through a Fn mediated-bridge. The FnBPA and FnBPB A domains engage in homophilic cell-cell interactions and promote biofilm formation and enhance platelet aggregation. In this review we update the current understanding of the structure and functional properties of FnBPs and emphasize the role they may have in the staphylococcal infections.

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Staphylococcus pseudintermedius Surface Protein L (SpsL) Is Required for Abscess Formation in a Murine Model of Cutaneous Infection

Cited by 14 publications

References 46 publications

Staphylococcal Protein A ( spa ) Locus Is a Hot Spot for Recombination and Horizontal Gene Transfer in Staphylococcus pseudintermedius

Staphylococcal Protein A ( spa ) Locus Is a Hot Spot for Recombination and Horizontal Gene Transfer in Staphylococcus pseudintermedius

Host-specialized fibrinogen-binding by a bacterial surface protein promotes biofilm formation and innate immune evasion

The Multivalent Role of Fibronectin-Binding Proteins A and B (FnBPA and FnBPB) of Staphylococcus aureus in Host Infections

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