N-Acetylglucosaminylation of Serine-Aspartate Repeat Proteins Promotes Staphylococcus aureus Bloodstream Infection

Thomer, Lena; Becker, Samuel H.; Emolo, Carla; Quach, Austin; Kim, Hwan Keun; Rauch, Sabine; Anderson, Mark; LeBlanc, James F.; Schneewind, Olaf; Faull, Kym F.; Missiakas, Dominique

doi:10.1074/jbc.m113.532655

Cited by 26 publications

(38 citation statements)

References 43 publications

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“…Marked increases were observed in expression of four genes associated with adhesion or matrix binding. Four genes (clfA, clfB, sdrC, and bbp) had previously been reported to mediate S. aureus binding to fibrin(ogen) (27,(38)(39)(40)(41). By upregulating these specific genes, S. aureus is apparently selectively enhancing its ability to associate with fibrin(ogen), a protein that is increased in abundance in the obese/T2D host as a component of the hypercoagulable state that is a complication of this disease.…”

Section: Discussionmentioning

confidence: 99%

Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence

et al. 2017

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Obesity and associated type 2 diabetes (T2D) are important risk factors for infection following orthopedic implant surgery. Staphylococcus aureus, the most common pathogen in bone infections, adapts to multiple environments to survive and evade host immune responses. Whether adaptation of S. aureus to the unique environment of the obese/T2D host accounts for its increased virulence and persistence in this population is unknown. Thus, we assessed implant-associated osteomyelitis in normal versus high-fat-diet obese/T2D mice and found that S. aureus infection was more severe, including increases in bone abscesses relative to nondiabetic controls. S. aureus isolated from bone of obese/T2D mice displayed marked upregulation of four adhesion genes (clfA, clfB, bbp, and sdrC), all with binding affinity for fibrin(ogen). Immunostaining of infected bone revealed increased fibrin deposition surrounding bacterial abscesses in obese/T2D mice. In vitro coagulation assays demonstrated a hypercoagulable state in obese/T2D mice that was comparable to that of diabetic patients. S. aureus with an inactivating mutation in clumping factor A (clfA) showed a reduction in bone infection severity that eliminated the effect of obesity/T2D, while infections in control mice were unchanged. In infected mice that overexpress plasminogen activator inhibitor-1 (PAI-1), S. aureus clfA expression and fibrin-encapsulated abscess communities in bone were also increased, further linking fibrin deposition to S. aureus expression of clfA and infection severity. Together, these results demonstrate an adaptation by S. aureus to obesity/T2D with increased expression of clfA that is associated with the hypercoagulable state of the host and increased virulence of S. aureus.

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Section: Discussionmentioning

confidence: 99%

Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence

et al. 2017

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“…S. aureus agglutinates with coagulase-derived fibrin fibrils, which requires clumping factor A (ClfA), a glycosylated, sortase-anchored surface protein whose immunoglobulin-like domains bind to the C-terminal end of the γ-chain in fibrinogen/fibrin (D domain) 96,100,101 (Fig. 2).…”

Section: Subversion Of Innate Immune Responsesmentioning

confidence: 99%

Staphylococcal manipulation of host immune responses

et al. 2015

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Staphylococcus aureus, a bacterial commensal of the human nares and skin, is a frequent cause of soft tissue and bloodstream infections. A hallmark of staphylococcal infections is their frequent recurrence, even when treated with antibiotics and surgical intervention, which demonstrates the bacterium’s ability to manipulate innate and adaptive immune responses. In this Review, we highlight how S. aureus virulence factors inhibit complement activation, block and destroy phagocytic cells and modify host B and T cell responses, and we discuss how these insights might be useful for the development of novel therapies against infections with antibiotic resistant strains such as methicillin-resistant S. aureus.

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“…In contrast to mutants lacking any one gene ( coa , vwb , or clfA ), which displayed reductions in virulence, a strain with all three genes deleted was avirulent in a mouse model of bloodstream infection, suggesting a synergistic mode of action between staphylococcal factors for hemostatic interference (87). Of note, ClfA and other S. aureus surface proteins with C-terminal serine-aspartate (SD) repeats are N -acetylglucosaminylated, posttranslational modifications that contribute to S. aureus agglutination in animal or human blood (92). The molecular mechanism whereby N -acetylglucosaminylation of SD repeat proteins contributes to staphylococcal agglutination is not known.…”

Section: Staphylococcal Interference With Hemostasismentioning

confidence: 99%

Pathogenesis of Staphylococcus aureus Bloodstream Infections

Thomer

Schneewind

Missiakas

2016

Annu. Rev. Pathol. Mech. Dis.

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229

196

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Staphylococcus aureus , a Gram-positive bacterium colonizing nares, skin, and the gastrointestinal tract, frequently invades the skin, soft tissues, and bloodstreams of humans. Even with surgical and antibiotic therapy, bloodstream infections are associated with significant mortality. The secretion of coagulases, proteins that associate with and activate the host hemostatic factor prothrombin, and the bacterial surface display of agglutinins, proteins that bind polymerized fibrin, are key virulence strategies for the pathogenesis of S. aureus bloodstream infections, which culminate in the establishment of abscess lesions. Pathogen-controlled processes, involving a wide spectrum of secreted factors, are responsible for the recruitment and destruction of immune cells, transforming abscess lesions into purulent exudate, with which staphylococci disseminate to produce new infectious lesions or to infect new hosts. Research on S. aureus bloodstream infections is a frontier for the characterization of protective vaccine antigens and the development of immune therapeutics aiming to prevent disease or improve outcomes.

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N-Acetylglucosaminylation of Serine-Aspartate Repeat Proteins Promotes Staphylococcus aureus Bloodstream Infection

Cited by 26 publications

References 43 publications

Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence

Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence

Staphylococcal manipulation of host immune responses

Pathogenesis of Staphylococcus aureus Bloodstream Infections

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