Staphylococcal Proteases Aid in Evasion of the Human Complement System

Jusko, Monika; Potempa, Jan; Kantyka, Tomasz; Bielecka, Ewa; Miller, Halie K.; Kalińska, Magdalena; Dubin, Grzegorz; Garred, Peter; Shaw, Lindsey N.; Blom, Anna M.

doi:10.1159/000351458

Cited by 82 publications

(62 citation statements)

References 42 publications

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“…This could potentially lead to the eradication of some complement-sensitive species and thus contribute to the dysbiosis of the plaque observed in the disease. In this regard, we observed that aureolysin of Staphylococcus aureus increases C1q opsonization of a commensal Staphylococcus epidermidis while limiting C1q level on S. aureus (26) Regarding alternative pathway, mirolysin, similar to karilysin, did not affect C3b deposition occurring via this pathway (Fig. 5A), but it targeted the initial step of terminal complement pathway, efficiently limiting C5b deposition (Fig.…”

Section: Discussionmentioning

confidence: 84%

A metalloproteinase mirolysin of Tannerella forsythia inhibits all pathways of the complement system

Jusko

Potempa

Książek

et al. 2013

Molecular Immunology

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Section: Discussionmentioning

confidence: 84%

A metalloproteinase mirolysin of Tannerella forsythia inhibits all pathways of the complement system

Jusko

Potempa

Książek

et al. 2013

Molecular Immunology

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“…Many immunomodulating mechanisms of the proteases have been identified (3), including effects on phagocyte chemotaxis and phagocytosis of S. aureus (37,(39)(40)(41)(42). Furthermore, the proteases have been shown to inactivate human protease inhibitors (e.g., ␣ 1 -antitrypsin), to cleave phagocyte "donot-eat-me" surface receptors (CD31), to inhibit complement activation (9), and to induce phagocyte cell death (42,43). We now add the processing of galectin-3 as a possible staphylococcal immunomodulating function.…”

Section: Discussionmentioning

confidence: 99%

Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus

Elmwall

Kwieciński

et al. 2017

Infect Immun

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Staphylococcus aureus is a major cause of skin and soft tissue infection. The bacterium expresses four major proteases that are emerging as virulence factors: aureolysin (Aur), V8 protease (SspA), staphopain A (ScpA), and staphopain B (SspB). We hypothesized that human galectin-3, a ␤-galactoside-binding lectin involved in immune regulation and antimicrobial defense, is a target for these proteases and that proteolysis of galectin-3 is a novel immune evasion mechanism. Indeed, supernatants from laboratory strains and clinical isolates of S. aureus caused galectin-3 degradation. Similar proteolytic capacities were found in Staphylococcus epidermidis isolates but not in Staphylococcus saprophyticus. Galectin-3-induced activation of the neutrophil NADPH oxidase was abrogated by bacterium-derived proteolysis of galectin-3, and SspB was identified as the major protease responsible. The impact of galectin-3 and protease expression on S. aureus virulence was studied in a murine skin infection model. In galectin-3 ϩ/ϩ mice, SspB-expressing S. aureus caused larger lesions and resulted in higher bacterial loads than protease-lacking bacteria. No such difference in bacterial load or lesion size was detected in galectin-3 Ϫ/Ϫ mice, which overall showed smaller lesion sizes than the galectin-3 ϩ/ϩ animals. In conclusion, the staphylococcal protease SspB inactivates galectin-3, abrogating its stimulation of oxygen radical production in human neutrophils and increasing tissue damage during skin infection.

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“…Human IgG was purchased from Immuno. Recombinant DAF with Fc tag was expressed and purified as described (41). IAPP was purchased from Caslo, Cambridge Research Biochemicals or synthesized and purified by Dr. James I. Elliott (Oxford, CT) and dissolved in DMSO at 20 -40 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

C4b-binding Protein Protects β-Cells from Islet Amyloid Polypeptide-induced Cytotoxicity

Sjölander

Byman

Kulak

et al. 2016

Journal of Biological Chemistry

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C4BP (C4b-binding protein) is a polymer of seven identical ␣ chains and one unique ␤ chain synthesized in liver and pancreas. We showed previously that C4BP enhances islet amyloid polypeptide (IAPP) fibril formation in vitro. Now we report that polymeric C4BP strongly inhibited lysis of human erythrocytes incubated with monomeric IAPP, whereas no lysis was observed after incubation with preformed IAPP fibrils. In contrast, incubation with the monomeric ␣-chain of C4BP was less effective. These data indicate that polymeric C4BP with multiple binding sites for IAPP neutralizes lytic activity of IAPP. The present study focuses on C4BP 2 (C4b-binding protein), which is an essential inhibitor of the complement system (1). Complement has important roles in innate immunity and consists of more than 40 proteins involved in initiation and control of the system (2). C4BP is an abundant polymeric plasma protein that consists of seven identical ␣-chains with eight complement control protein (CCP) domains each, as well as one ␤-chain with three CCPs. The ␤-chain always carries anticoagulant PS (protein S) (3). Because of the high affinity of PS for negatively charged phospholipids, the C4BP-PS complex efficiently binds to apoptotic (4) and necrotic cells (5), ensuring controlled complement activation necessary for clearance of these cells. So far, C4BP has been characterized in detail as a complement inhibitor and is often employed by bacterial pathogens as a form of evasion strategy leading to decreased opsonization and phagocytosis (6). C4BP may have other immunomodulatory functions such as the induction of an antiinflammatory state in dendritic cells (7). Complete deficiency of C4BP has not been described, but non-synonymous polymorphisms causing impaired complement inhibitory activity were found in atypical hemolytic uremic syndrome (8) and recurrent, spontaneous pregnancy loss (9). C4BP is mainly secreted by hepatocytes but significant expression is also detected in lung and pancreatic islets. We found previously that C4BP interacts with various types of amyloid (10 -12), which similarly to in dying cells, allows a certain level of complement opsonization for clearance while preventing overt inflammation.In type 2 diabetes amyloid deposits are localized to the islets of Langerhans in the pancreas and mainly formed by islet amyloid polypeptide (IAPP). IAPP deposits are present in 90% of patients with type 2 diabetes and can cause apoptosis of ␤-cells (13). Apart from this cytotoxic effect IAPP also has a physiological role in regulating and stabilizing blood glucose levels. When insulin resistance develops in type 2 diabetes, so does the production and release of insulin and concomitantly IAPP in the ␤-cell (14, 15). Once IAPP reaches a critical concentration, it starts to aggregate. The small aggregates form ␤-sheet-rich proto-filaments that interact with each other and eventually form mature fibrils. Even though the exact cytotoxic form of IAPP (monomers, oligomers, or fibrils) is still discussed, there is a growing co...

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Staphylococcal Proteases Aid in Evasion of the Human Complement System

Cited by 82 publications

References 42 publications

A metalloproteinase mirolysin of Tannerella forsythia inhibits all pathways of the complement system

A metalloproteinase mirolysin of Tannerella forsythia inhibits all pathways of the complement system

Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus

C4b-binding Protein Protects β-Cells from Islet Amyloid Polypeptide-induced Cytotoxicity

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