Staphylococcal Superantigen-like Protein 10 (SSL10) Inhibits Blood Coagulation by Binding to Prothrombin and Factor Xa via Their γ-Carboxyglutamic Acid (Gla) Domain

Itoh, Saotomo; Yokoyama, Ryosuke; Kamoshida, Go; Fujiwara, Toshinobu; Okada, Hiromi; Takii, Takemasa; Tsuji, Tsutomu; Fujii, Satoshi; Hashizume, Hidetoshi; Onozaki, Kikuo

doi:10.1074/jbc.m113.451419

Cited by 38 publications

(39 citation statements)

References 24 publications

(33 reference statements)

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“…Soluble protein was purified by metal chelation chromatography with TALON 1 resin (Clonetech Laboratories Inc, Mountain View, CA, USA), yielding recombinant protein with a histadine tag on the N-terminus and a single biotin on the C-terminus. For the production of coagulase, a glutathione S-transferase-tag was added on the N-terminus to minimize proteolysis; the glutathione S-transferase-tag was removed after purification [19,27]. Purity and correct molecular weight were measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) (Fig.…”

Section: Animal Seramentioning

confidence: 99%

A Diagnostic Serum Antibody Test for Patients With Staphylococcus aureus Osteomyelitis

Nishitani

Beck

Rosenberg

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Because immunity against Staphylococcus aureus has not been fully elucidated, there is no diagnostic test to gauge how robust a patient's host response is likely to be. Therefore, we aimed to develop a test for specific antibodies in serum with diagnostic and prognostic potential. Questions/Purposes We describe the development and validation of a multiplex immunoassay for characterizing a patient's immune response against 14 known S aureus antigens, which we then used to answer four questions: (1) Do certain antigens predominate in the immune response against S aureus? (2) Is there a predominant pattern of antigens recognized by patients and mice with infections? (3) Is the immunoglobulin G (IgG) response to any single antigen a useful predictor of ongoing S aureus infection? (4) Does measurement of the combined response against all 14 antigens provide a better predictor of ongoing infection? Methods A case-control study was performed. Sera were collected from 35 consecutive patients with S aureus culture-confirmed (methicillin-sensitive S aureus or methicillin-resistant S aureus) musculoskeletal infections The institution of one or more of the authors (EMS, SLK, JLD, CAB) has received, during the study period, funding from the National Institutes of Health, NIAMS (Bethesda, MD, USA) and (EMS, SLK, JLD) the AOTrauma Clinical Priority Program (Davos, Switzerland). One of the authors certifies that he (JLD) or she or a member of his or her immediate family, has received or may receive payments or benefits, during the study period, an amount of USD 10,000 to 100,000 from Telephus Medical LLC (San Diego, CA, USA) and an amount of less than USD 10,000 from Calorics Pharmaceuticals (Waltham, MA, USA). One of the authors certifies that he (EMS) or she or a member of his or her immediate family, has received or may receive payments or benefits, during the study period, an amount of USD 10,000 to 100,000 from Telephus Medical LLC (San Diego, CA, USA). One of the authors certifies that he (SLK) or she or a member of his or her immediate family, has received or may receive payments or benefits, during the study period, an amount of less than USD 10,000 from Surgical Excellence Healthcare Quality Consulting, and an amount of USD 10,000 to 100,000 from Sage Publications (Thousand Oaks, CA, USA) One of the authors certifies that he (CAB) or she or a member of his or her immediate family, has received or may receive payments or benefits, during the study period, an amount of USD 10,000 to 100,000 from the FDA (Silver Spring, MD, USA), and an amount of USD 10,000 to 100,000 from Boston Scientific (Marlborough, MA, USA), an amount of USD 10,000 to 100,000 from Lundbeck Inc (Deerfield, IL, USA), an amount of USD 10,000 to 100,000 from Patient-Centered Outcomes Research Institute (PCORI, Washington, DC, USA), and an amount of less than USD 10,000 from Auspex Pharmaceuticals (La Jolla, CA, USA). All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research 1 editors and board mem...

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Section: Animal Seramentioning

confidence: 99%

A Diagnostic Serum Antibody Test for Patients With Staphylococcus aureus Osteomyelitis

Nishitani

Beck

Rosenberg

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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“…Interestingly, the functions that have been discovered for SSLs so far have all been linked to immune evasion. SSL5 inhibits neutrophil extravasation (17,18) and phagocyte function (19,20), SSL7 binds IgA and inhibits complement (21), and SSL10 inhibits IgG1-mediated phagocytosis (22,23), blood coagulation (24), and the chemokine receptor CXCR4 (25). In addition to SSL3, also weak TLR2 inhibitory activity was observed for SSL4 (5), but it remains unknown whether that is its dominant function.…”

mentioning

confidence: 99%

Structural basis for inhibition of TLR2 by staphylococcal superantigen-like protein 3 (SSL3)

Koymans

Feitsma

Brondijk

et al. 2015

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

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Toll-like receptors (TLRs) are crucial in innate recognition of invading micro-organisms and their subsequent clearance. Bacteria are not passive bystanders and have evolved complex evasion mechanisms. Staphylococcus aureus secretes a potent TLR2 antagonist, staphylococcal superantigen-like protein 3 (SSL3), which prevents receptor stimulation by pathogen-associated lipopeptides. Here, we present crystal structures of SSL3 and its complex with TLR2. The structure reveals that formation of the specific inhibitory complex is predominantly mediated by hydrophobic contacts between SSL3 and TLR2 and does not involve interaction of TLR2-glycans with the conserved Lewis X binding site of SSL3. In the complex, SSL3 partially covers the entrance to the lipopeptide binding pocket in TLR2, reducing its size by ∼50%. We show that this is sufficient to inhibit binding of agonist Pam 2 CSK 4 effectively, yet allows SSL3 to bind to an already formed TLR2-Pam 2 CSK 4 complex. The binding site of SSL3 overlaps those of TLR2 dimerization partners TLR1 and TLR6 extensively. Combined, our data reveal a robust dual mechanism in which SSL3 interferes with TLR2 activation at two stages: by binding to TLR2, it blocks ligand binding and thus inhibits activation. Second, by interacting with an already formed TLR2-lipopeptide complex, it prevents TLR heterodimerization and downstream signaling.S. aureus | Toll-like receptor | immune evasion | innate immunity | crystal structure

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“…SSL10 binds 1:1 with immunoglobulin of the IgG1 subclass with an affinity of 300 nM and a specificity that is restricted to human and primates [376,377]. Binding of SSL10 to fibrinogen, fibronectin [377], CXCR4 [378], phosphatidylserine [379], prothrombin, and factor Xa [380] has also been observed. SSL10 secreted by S. aureus into its immediate environment binds to IgG1, the most abundant of the four human IgG subclasses found in the blood which also has the highest affinity for multiple FcγRs [390].…”

Section: The Immunoglobulin/complement-inhibiting Sslsmentioning

confidence: 86%

“…Further binding interactions are seen to the platelet glycoprotein GPIbα, the platelet integrin αIIbβ3 (GPIIb-IIIa), and the platelet collagen receptor GPVI, resulting in platelet activation and aggregation [370,372]. Together with the ability of SSL10 to inhibit coagulation of blood by binding to prothrombin and factor Xa [380], this may convey additional advantages to S. aureus during infection and immune evasion. SSL5 is implicated in contributing to the disseminated intravascular coagulation (DIC) associated with S. aureus as a consequence of its interaction with platelets [397].…”

Section: The Sialylated Glycan-binding Sslsmentioning

confidence: 95%

Bacterial superantigens and superantigen-like toxins

Langley

Fraser

Proft

2015

The Comprehensive Sourcebook of Bacterial Protein Toxins

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Staphylococcal Superantigen-like Protein 10 (SSL10) Inhibits Blood Coagulation by Binding to Prothrombin and Factor Xa via Their γ-Carboxyglutamic Acid (Gla) Domain

Cited by 38 publications

References 24 publications

A Diagnostic Serum Antibody Test for Patients With Staphylococcus aureus Osteomyelitis

A Diagnostic Serum Antibody Test for Patients With Staphylococcus aureus Osteomyelitis

Structural basis for inhibition of TLR2 by staphylococcal superantigen-like protein 3 (SSL3)

Bacterial superantigens and superantigen-like toxins

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