3D Structural View of Pathogen Recognition by Mammalian Lectin Receptors

Humans and other mammals resist exogenous pathogens by recognizing them as non-self. How do they do this? The answer lies in the recognition by mammalian lectin receptors of glycans usually found on the surface of pathogens and whose chemical structure is species-specific. Some glycan components, such as galactofuranose, only occur in microbes, and is the principal means by which mammalian lectin receptors recognize non-self. Several lectins may function together as pattern recognition receptors to survey the infecting pathogen before the adaptive immune system is invoked. Most lectins have primary and secondary monosaccharide-binding sites which together determine the specificity of a receptor toward microbial glycans. There may also be a hydrophobic groove alongside the sugar binding sites that increases specificity. Another elaboration is through oligomerization of lectin domains with defined spacing and arrangement that creates high-affinity binding towards multiply-presented glycans on microbes. Microbe-specific polysaccharides may arise through unique sugar linkages. Specificity can come from mammalian receptors possessing a shallow binding site and binding only internal disaccharide units, as in the recognition of mannan by Dectin-2. The accumulation of 3D structural information on lectins receptors has allowed the recognition modes of microbe glycans to be classified into several groupings. This review is an introduction to our current knowledge on the mechanisms of pathogen recognition by representative mammalian lectin receptors.

Mammalian lectin arrays for screening host–microbe interactions

Many members of the C-type lectin family of glycan-binding receptors have been ascribed roles in the recognition of microorganisms and serve as key receptors in the innate immune response to pathogens. Other mammalian receptors have become targets through which pathogens enter target cells. These receptor roles have often been documented with binding studies involving individual pairs of receptors and microorganisms. To provide a systematic overview of interactions between microbes and the large complement of C-type lectins, here we developed a lectin array and suitable protocols for labeling of microbes that could be used to probe this array. The array contains C-type lectins from cow, chosen as a model organism of agricultural interest for which the relevant pathogen–receptor interactions have not been previously investigated in detail. Screening with yeast cells and various strains of both Gram-positive and -negative bacteria revealed distinct binding patterns, which in some cases could be explained by binding to lipopolysaccharides or capsular polysaccharides, but in other cases they suggested the presence of novel glycan targets on many of the microorganisms. These results are consistent with interactions previously ascribed to the receptors, but they also highlight binding to additional sugar targets that have not previously been recognized. Our findings indicate that mammalian lectin arrays represent unique discovery tools for identifying both novel ligands and new receptor functions.

The mammalian lectin galectin-8 induces RANKL expression, osteoclastogenesis, and bone mass reduction in mice

Skeletal integrity is maintained by the co-ordinated activity of osteoblasts, the bone-forming cells, and osteoclasts, the bone-resorbing cells. In this study, we show that mice overexpressing galectin-8, a secreted mammalian lectin of the galectins family, exhibit accelerated osteoclasts activity and bone turnover, which culminates in reduced bone mass, similar to cases of postmenopausal osteoporosis and cancerous osteolysis. This phenotype can be attributed to a direct action of galectin-8 on primary cultures of osteoblasts that secrete the osteoclastogenic factor RANKL upon binding of galectin-8. This results in enhanced differentiation into osteoclasts of the bone marrow cells co-cultured with galectin-8-treated osteoblasts. Secretion of RANKL by galectin-8-treated osteoblasts can be attributed to binding of galectin-8 to receptor complexes that positively (uPAR and MRC2) and negatively (LRP1) regulate galectin-8 function. Our findings identify galectins as new players in osteoclastogenesis and bone remodeling, and highlight a potential regulation of bone mass by animal lectins.