The bacteria binding glycoprotein salivary agglutinin (SAG/gp340) activates complement via the lectin pathway

Leito, Jelani T.D.; Ligtenberg, A.J.M.; Houdt, Michel van; Berg, Timo K. van den; Wouters, Diana

doi:10.1016/j.molimm.2011.08.010

Cited by 50 publications

(53 citation statements)

References 32 publications

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“…Indeed, it can stimulate a dose-dependent chemokinesis (random migration) of alveolar macrophages, suggesting role(s) in respiratory inflammatory and immune responses [46]. It is also able to activate classical and lectin pathways of the complement system [62, 63]. Teasing apart the relative contributions of different DMBT1 activities in protecting the cornea against P .…”

Section: Discussionmentioning

confidence: 99%

Mucosal fluid glycoprotein DMBT1 suppresses twitching motility and virulence of the opportunistic pathogen Pseudomonas aeruginosa

Metruccio

Evans

et al. 2017

PLoS Pathog

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It is generally thought that mucosal fluids protect underlying epithelial surfaces against opportunistic infection via their antimicrobial activity. However, our published data show that human tear fluid can protect against the major opportunistic pathogen Pseudomonas aeruginosa independently of bacteriostatic activity. Here, we explored the mechanisms for tear protection, focusing on impacts of tear fluid on bacterial virulence factor expression. Results showed that tear fluid suppressed twitching motility, a type of surface-associated movement conferred by pili. Previously, we showed that twitching is critical for P. aeruginosa traversal of corneal epithelia, exit from epithelial cells after internalization, and corneal virulence. Inhibition of twitching by tear fluid was dose-dependent with dilutions to 6.25% retaining activity. Purified lactoferrin, lysozyme, and contrived tears containing these, and many other, tear components lacked the activity. Systematic protein fractionation, mass spectrometry, and immunoprecipitation identified the glycoprotein DMBT1 (Deleted in Malignant Brain Tumors 1) in tear fluid as required. DMBT1 purified from human saliva also inhibited twitching, as well as P. aeruginosa traversal of human corneal epithelial cells in vitro, and reduced disease pathology in a murine model of corneal infection. DMBT1 did not affect PilA expression, nor bacterial intracellular cyclicAMP levels, and suppressed twitching motility of P. aeruginosa chemotaxis mutants (chpB, pilK), and an adenylate cyclase mutant (cyaB). However, dot-immunoblot assays showed purified DMBT1 binding of pili extracted from PAO1 suggesting that twitching inhibition may involve a direct interaction with pili. The latter could affect extension or retraction of pili, their interactions with biotic or abiotic surfaces, or cause their aggregation. Together, the data suggest that DMBT1 inhibition of twitching motility contributes to the mechanisms by which mucosal fluids protect against P. aeruginosa infection. This study also advances our understanding of how mucosal fluids protect against infection, and suggests directions for novel biocompatible strategies to protect our surface epithelia against a major opportunistic pathogen.

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Section: Discussionmentioning

confidence: 99%

Mucosal fluid glycoprotein DMBT1 suppresses twitching motility and virulence of the opportunistic pathogen Pseudomonas aeruginosa

Metruccio

Evans

et al. 2017

PLoS Pathog

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“…It was previously shown that SAG binds to MBL [15,33], which is one of the recognition molecules of the lectin pathway of the complement system that recognises carbohydrate structures on pathogens and altered-self cells [34]. The fucose moieties present on SAG are critical for binding to MBL, and this binding activates the lectin pathway of the complement system [19,33]. Besides MBL, another binding partner of SAG is C1q, the recognition molecule of the classical pathway of the complement system [14].…”

Section: Discussionmentioning

confidence: 99%

The Human Glycoprotein Salivary Agglutinin Inhibits the Interaction of DC-SIGN and Langerin with Oral Micro-Organisms

Boks

Gunput²,

Kosten³

et al. 2016

J Innate Immun

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Salivary agglutinin (SAG), also known as gp340 or SALSA, is a glycoprotein encoded by the Deleted in Malignant Brain Tumours 1 gene and is abundantly present in human saliva. SAG aggregates bacteria and viruses, thereby promoting their clearance from the oral cavity. The mucosa lining the oral cavity contains dendritic cells (DC) and Langerhans cells (LC), which express the C-type lectin receptors (CLR) DC-SIGN and Langerin, respectively. Both DC-SIGN and Langerin recognise mannose and fucose carbohydrate structures on pathogens and self-glycoproteins to regulate immunity and homeostasis. The purpose of this study was to investigate whether SAG interacts with these CLR and whether this interferes with the binding to oral pathogens. We show that whole parotid saliva and SAG, when coated to microplates, strongly interact with DC-SIGN and Langerin, probably via mannose and fucose structures. Also, primary human DC and LC bind parotid saliva and SAG via DC-SIGN and Langerin, respectively. Furthermore, SAG binding to DC-SIGN or Langerin prevented binding to the micro-organisms Candida albicans and Escherichia coli which express mannose and fucose-containing glycan structures. Thus, binding of saliva glycoprotein SAG to DC-SIGN and Langerin may inhibit pathogen-DC/LC interactions, and could prove to be a new immunomodulatory mechanism of SAG.

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“…This was observed by utilizing an assay measuring disappearance of native C4 and appearance of C4b in a Western blot assay (Boackle et al, 1993). Another study showed activation of complement through the lectin pathway (Leito et al, 2011). Since we had initially observed inhibition of the lectin pathway we now investigated the overall effect of SALSA on complement activation.…”

Section: Discussionmentioning

confidence: 99%

The salivary scavenger and agglutinin binds MBL and regulates the lectin pathway of complement in solution and on surfaces

et al. 2012

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The salivary scavenger and agglutinin (SALSA), also known as gp340, salivary agglutinin and deleted in malignant brain tumor 1, is a 340-kDa glycoprotein expressed on mucosal surfaces and secreted into several body fluids. SALSA binds to a broad variety of microbes and endogenous ligands, such as complement factor C1q, surfactant proteins D and A, and IgA. Our search for novel ligands of SALSA by direct protein-interaction studies led to the identification of mannan-binding lectin (MBL) as a new binding partner. We observed that surface-associated SALSA activates complement via binding of MBL. On the other hand, soluble SALSA was found to inhibit Candida albicans-induced complement activation. Thus, SALSA has a dual complement activation modifying function. It activates the lectin pathway when bound to a surface and inhibits it when free in the fluid phase. These activities are mediated via a direct interaction with MBL. This suggests that SALSA could target the innate immune responses to certain microorganisms and simultaneously limit complement activation in the fluid phase.

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The bacteria binding glycoprotein salivary agglutinin (SAG/gp340) activates complement via the lectin pathway

Cited by 50 publications

References 32 publications

Mucosal fluid glycoprotein DMBT1 suppresses twitching motility and virulence of the opportunistic pathogen Pseudomonas aeruginosa

Mucosal fluid glycoprotein DMBT1 suppresses twitching motility and virulence of the opportunistic pathogen Pseudomonas aeruginosa

The Human Glycoprotein Salivary Agglutinin Inhibits the Interaction of DC-SIGN and Langerin with Oral Micro-Organisms

The salivary scavenger and agglutinin binds MBL and regulates the lectin pathway of complement in solution and on surfaces

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