Galectin-3 bindsNeisseria meningitidisand increases interaction with phagocytic cells

Abstract

Summary Galectin‐3 is expressed and secreted by immune cells and has been implicated in multiple aspects of the inflammatory response. It is a glycan binding protein which can exert its functions within cells or exogenously by binding cell surface ligands, acting as a molecular bridge or activating signalling pathways. In addition, this lectin has been shown to bind to microorganisms. In this study we investigated the interaction between galectin‐3 and Neisseria meningitidis, an important extracellular human pathogen, which is a leading cause of septicaemia and meningitis. Immunohistochemical analysis indicated that galectin‐3 is expressed during meningococcal disease and colocalizes with bacterial colonies in infected tissues from patients. We show that galectin‐3 binds to N. meningitidis and we demonstrate that this interaction requiresfull‐length, intact lipopolysaccharide molecules. We found that neither exogenous nor endogenous galectin‐3 contributes to phagocytosis of N. meningitidis; instead exogenous galectin‐3 increases adhesion to monocytes and macrophages but not epithelial cells. Finally we used galectin‐3 deficient (Gal‐3−/−) mice to evaluate the contribution of galectin‐3 to meningococcal bacteraemia. We found that Gal‐3−/− mice had significantly lower levels of bacteraemia compared with wild‐type mice after challenge with live bacteria, indicating that galectin‐3 confers an advantage to N. meningitidis during systemic infection.

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

“…These suggested mechanisms can appear to work in opposite directions, but opposing functions are well-known phenomena in the galectin field. For example, systemic Neisseria infection is dampened in Gal-3 knockout mice, while streptococcal pneumonia is instead significantly enhanced (14,15). Furthermore, galectin-3 may have several different functions in one and the same model (15), and it is not always clear how the combination of different mechanisms ends up giving the result achieved (11).…”

“…Neutrophil activation by galectin-3, enhanced after extravasation of the cells into tissue, may contribute to tissue destruction by the production of toxic oxygen radicals and cytokines and the release of neutrophil proteases (15,22,25). Another mechanism could involve the cleavage of galectin-3 by SspB (as shown here) and by neutrophil-released metalloproteases and serine proteases (25,27,28), impairing the production of immunomodulatory ROS, as well as galectin-3-dependent opsonophagocytic processes, possibly resulting in impaired infection control and aggravated tissue destruction (14,15,24). Furthermore, protease-cleaved galectin-3 (CRD) may possibly have proinflammatory effects per se, contributing to inflammatory tissue damage, as seen in other disease models (51)(52)(53)(54).…”

“…The epithelial damage by the bacteria per se, enhanced by protease expression, induces an augmented inflammatory activation and recruitment of neutrophils, the most important cell type in fighting S. aureus skin infection (3). Neutrophil migration into infected tissue has previously been shown to be affected by galectin-3 (16,50), which is produced in increased amounts during infectious/inflammatory processes (14,16). Neutrophil activation by galectin-3, enhanced after extravasation of the cells into tissue, may contribute to tissue destruction by the production of toxic oxygen radicals and cytokines and the release of neutrophil proteases (15,22,25).…”

“…It exhibits significant regulatory functions both in host defense against infection and in aseptic inflammation (11)(12)(13). Several findings suggest that galectin-3 participates in antimicrobial defense, having opsonizing and bacteriostatic properties or inducing infection-reducing effects in the host (14)(15)(16), but there are also data showing that galectin-3 can contribute to microbial pathogenesis, e.g., by promoting adhesion to host cells or increasing the tissue-destructive response of inflammatory cells (14,15,17,18). Galectin-3 is produced in epithelia and by several immune cells and is released by monocytes and macrophages in response to bacterial lipopolysaccharide (19,20).…”

“…In addition to the CRD, galectin-3 has a collagen-like N-domain that is sensitive to proteolytic cleavage (25). This N-domain is essential for oligomerization of galectin-3 and for many of the galectin-3-induced effects in inflammation (14,22,26). There are proteases known to cleave galectin-3; human neutrophil elastase and matrix metalloproteinases-2, -7, and -9 can proteolytically process the lectin (25,27,28), a feature shared by proteases from protozoa (29) and bacteria (26,30,31).…”