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Design of a Cytotoxic Neuroblastoma-Targeting Agent Using an Enzyme Acting on Polysialic Acid Fused to a Toxin.

Polysialic acid, an abundant cell surface component of the developing nervous system, which declines rapidly postnatally to virtual absence in the majority of adult tissues, is highly expressed in some malignant tumors including neuroblastoma. We found that the binding of a noncatalytic endosialidase to polysialic acid causes internalization of the complex from the surface of neuroblastoma kSK-N-SH cells, a subline of SK-N-SH, and leads to a complete relocalization of polysialic acid to the intracellular compartment. The binding and uptake of the endosialidase is polysialic acid-dependent as it is inhibited by free excess ligand or removal of polysialic acid by active endosialidase, and does not happen if catalytic endosialidase is used in place of inactive endosialidase.

The binding mechanism of the virulence factor adhesin P subtype to globotetraosylceramide is associated with systemic disease.

is part of the pig commensal microbiome but strains can also be pathogenic, causing pneumonia and meningitis in pigs as well as zoonotic meningitis. According to genomic analysis, is divided into asymptomatic carriage, respiratory and systemic strains with distinct genomic signatures. Because the strategies to target pathogenic are limited, new therapeutic approaches are needed.

Internalization of a polysialic acid-binding Escherichia coli bacteriophage into eukaryotic neuroblastoma cells.

Eukaryotic organisms are continuously exposed to bacteriophages, which are efficient gene transfer agents in bacteria. However, bacteriophages are considered not to pass the eukaryotic cell membrane and enter nonphagocytic cells. Here we report the binding and penetration of Escherichia coli PK1A2 bacteriophage into live eukaryotic neuroblastoma cells in vitro.

Rationally Designed Chemically Modified Glycodendrimer Inhibits Streptococcus suis Adhesin SadP at Picomolar Concentrations.

Host cell surface carbohydrate receptors of bacterial adhesins are attractive targets in anti-adhesion therapy. The affinity of carbohydrate ligands with adhesins is usually found in the low μm range, which poses a problem for the design of effective inhibitors useful in therapy. In an attempt to increase the inhibitory power of carbohydrate ligands, we have combined the approach of chemical modification of ligands with their presentation as multivalent dendrimers in the design of an inhibitor of streptococcal adhesin SadP binding to its galactosyl-α1-4-galactose (galabiose) receptor.

Expression of neural cell adhesion molecule and polysialic acid in human bone marrow-derived mesenchymal stromal cells.

Background: In order to develop novel clinical applications and to gain insights into possible therapeutic mechanisms, detailed molecular characterization of human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) is needed. Neural cell adhesion molecule (NCAM, CD56) is a transmembrane glycoprotein modulating cell-cell and cell-matrix interactions. An additional post-translational modification of NCAM is the α2,8-linked polysialic acid (polySia).

Polysialic acid is associated with better prognosis and IDH1-mutation in diffusely infiltrating astrocytomas.

Background: The aim of the study was to assess the localization of Polysialic acid (polySia) and Neural cell adhesion molecule (NCAM) in grade I-IV astrocytomas by confocal microscopy, and also to clarify and compare their relationship to conventional clinicopathological features in these tumors.

Methods: Study material was stained immunohistochemically for polySia, NCAM and IDH1-R132H point mutation. Confocal microscopy of polySia and NCAM staining was performed on tissue micro-array samples (TMA) of 242 diffusely infiltrating astrocytomas (grade II: 28; grade III: 33; grade IV: 181) and 82 pilocytic astrocytomas.

Changes in polysialic acid expression on myeloid cells during differentiation and recruitment to sites of inflammation: role in phagocytosis.

Polysialic acid (polySia) is a unique linear homopolymer of α2,8-linked sialic acid that has been studied extensively as a posttranslational modification of neural cell adhesion molecule in the central nervous system. Only two proteins are known to be polysialylated in cells of the immune system: CD56 on human natural killer cells and murine bone marrow (BM) leukocytes, and neuropilin-2 (NRP-2) on dendritic cells (DCs). We tested the hypothesis that polySia expression is regulated during maturation and migration of leukocytes and plays a role in functional activity.

Expression, purification and crystallization of the C-terminal LRR domain of Streptococcus pyogenes protein 0843.

Streptococcus pyogenes protein 0843 (Spy0843) is a recently identified protein with a potential adhesin function. Sequence analysis has shown that Spy0843 contains two leucine-rich repeat (LRR) domains that mediate interactions with the gp340 receptor. Here, the C-terminal LRR domain was overexpressed in Escherichia coli, purified and crystallized in the presence of 1.

Bacterial Adhesion of Streptococcus suis to Host Cells and Its Inhibition by Carbohydrate Ligands.

Streptococcus suis is a Gram-positive bacterium, which causes sepsis and meningitis in pigs and humans. This review examines the role of known S. suis virulence factors in adhesion and S.

Use of tetravalent galabiose for inhibition of streptococcus suis serotype 2 infection in a mouse model.

Streptococcus suis is an important swine pathogen associated with a variety of infections such as meningitis, arthritis and septicemia. The bacterium is zoonotic and has been found to cause meningitis especially in humans occupationally exposed to infected pigs. Since adhesion is a prerequisite for colonization and subsequent infection, anti-adhesion treatment seems a natural alternative to traditional treatment with antibiotics.

Multivalent glycoconjugates as anti-pathogenic agents.

Multivalency plays a major role in biological processes and particularly in the relationship between pathogenic microorganisms and their host that involves protein-glycan recognition. These interactions occur during the first steps of infection, for specific recognition between host and bacteria, but also at different stages of the immune response. The search for high-affinity ligands for studying such interactions involves the combination of carbohydrate head groups with different scaffolds and linkers generating multivalent glycocompounds with controlled spatial and topology parameters.

Endosialidases: Versatile Tools for the Study of Polysialic Acid.

Polysialic acid is an α2,8-linked N-acetylneuraminic acid polymer found on the surface of both bacterial and eukaryotic cells. Endosialidases are bacteriophage-borne glycosyl hydrolases that specifically cleave polysialic acid. The crystal structure of an endosialidase reveals a trimeric mushroom-shaped molecule which, in addition to the active site, harbors two additional polysialic acid binding sites.

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

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.

Metabolism of vertebrate amino sugars with N-glycolyl groups: resistance of α2-8-linked N-glycolylneuraminic acid to enzymatic cleavage.

The sialic acid (Sia) N-acetylneuraminic acid (Neu5Ac) and its hydroxylated derivative N-glycolylneuraminic acid (Neu5Gc) differ by one oxygen atom. CMP-Neu5Gc is synthesized from CMP-Neu5Ac, with Neu5Gc representing a highly variable fraction of total Sias in various tissues and among different species. The exception may be the brain, where Neu5Ac is abundant and Neu5Gc is reported to be rare.

Glutamine synthetase and glucose-6-phosphate isomerase are adhesive moonlighting proteins of Lactobacillus crispatus released by epithelial cathelicidin LL-37.

Glutamine synthetase (GS) and glucose-6-phosphate isomerase (GPI) were identified as novel adhesive moonlighting proteins of Lactobacillus crispatus ST1. Both proteins were bound onto the bacterial surface at acidic pHs, whereas a suspension of the cells to pH 8 caused their release into the buffer, a pattern previously observed with surface-bound enolase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of L. crispatus.

Identification of a novel streptococcal adhesin P (SadP) protein recognizing galactosyl-α1-4-galactose-containing glycoconjugates: convergent evolution of bacterial pathogens to binding of the same host receptor.

Bacterial adhesion is often a prerequisite for infection, and host cell surface carbohydrates play a major role as adhesion receptors. Streptococci are a leading cause of infectious diseases. However, only few carbohydrate-specific streptococcal adhesins are known.

Ncam1a and Ncam1b: two carriers of polysialic acid with different functions in the developing zebrafish nervous system.

Polysialic acid (polySia) is mainly described as a glycan modification of the neural cell adhesion molecule NCAM1. PolySia-NCAM1 has multiple functions during the development of vertebrate nervous systems including axon extension and fasciculation. Phylogenetic analyses reveal the presence of two related gene clusters, NCAM1 and NCAM2, in tetrapods and fishes.

Magnetic properties and structural characterization of iron oxide nanoparticles formed by Streptococcus suis Dpr and four mutants.

Streptococcus suis Dpr belongs to the Dps family of bacterial and archaeal proteins that oxidize Fe(2+) to Fe(3+) to protect microorganisms from oxidative damage. The oxidized iron is subsequently deposited as ferrihydrite inside a protein cavity, resulting in the formation of an iron core. The size and the magnetic properties of the iron core have attracted considerable attention for nanotechnological applications in recent years.

Detection of pathogenic Streptococcus suis bacteria using magnetic glycoparticles.

Detection of the zoonotic bacterial pathogen Streptococcus suis was achieved using magnetic glycoparticles. The bacteria contain an adhesion protein for the carbohydrate sequence Galalpha1,4Gal. After incubation with various amounts of the pathogen, magnetic concentration and ATP detection, bacterial levels down to 10(5) cfu could be detected.

Screening of binding activity of Streptococcus pneumoniae, Streptococcus agalactiae and Streptococcus suis to berries and juices.

Antiadhesion therapy is a promising approach to the fight against pathogens. Antibiotic resistance and the lack of effective vaccines have increased the search for new methods to prevent infectious diseases. Previous studies have shown the antiadhesion activity of juice from cultivated cranberries (Vaccinium macrocarpon Ait.

Leucine-rich repeats of bacterial surface proteins serve as common pattern recognition motifs of human scavenger receptor gp340.

Scavenger receptors are innate immune molecules recognizing and inducing the clearance of non-host as well as modified host molecules. To recognize a wide pattern of invading microbes, many scavenger receptors bind to common pathogen-associated molecular patterns, such as lipopolysaccharides and lipoteichoic acids. Similarly, the gp340/DMBT1 protein, a member of the human scavenger receptor cysteine-rich protein family, displays a wide ligand repertoire.

Absence of polysialylated NCAM is an unfavorable prognostic phenotype for advanced stage neuroblastoma.

Background: The expression of a neural crest stem cell marker, polysialic acid (polySia), and its main carrier, neural cell adhesion molecule (NCAM), have been detected in some malignant tumors with high metastatic activity and unfavorable prognosis, but the diagnostic and prognostic value of polySia-NCAM in neuroblastoma is unclear.

Methods: A tumor tissue microarray (TMA) of 36 paraffin-embedded neuroblastoma samples was utilized to detect polySia-NCAM expression with a polySia-binding fluorescent fusion protein, and polySia-NCAM expression was compared with clinical stage, age, MYCN amplification status, histology (INPC), and proliferation index (PI).

Results: PolySia-NCAM-positive neuroblastoma patients had more often metastases at diagnosis, and polySia-NCAM expression associated with advanced disease (P = 0.

Differential expression of the polysialyl capsule during blood-to-brain transit of neuropathogenic Escherichia coli K1.

Escherichia coli K1 isolates synthesize a polysialic acid (polySia) capsule, are components of the adult gastrointestinal microbiota and may cause lethal bacteraemia and meningitis if acquired maternally by newborn infants. We used a neonatal rat pup K1 infection model to establish that prompt administration of a selective capsule depolymerase reverses the bacteraemic state and prevents death of almost all pups. In untreated animals, bacteria colonize the gastrointestinal tract and gain entry to the blood compartment, where they express the non-O-acetylated form of polySia.

Structural basis of the zinc- and terbium-mediated inhibition of ferroxidase activity in Dps ferritin-like proteins.

Streptococcus suis Dpr is an iron-binding protein involved in oxidative stress resistance. It belongs to the bacterial Dps protein family whose members form dodecameric assemblies. Previous studies have shown that zinc and terbium inhibit iron incorporation in Listeria innocua Dps protein.