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Thromboembolic complications are common in severe COVID-19 and are thought to result from excessive neutrophil-extracellular-trap (NET)-driven immunothrombosis. Glycosylation plays a vital role in the efficiency of immunoglobulin A (IgA) effector functions, with significant implications for NET formation in infectious diseases. This study represents the first comprehensive analysis of plasma IgA glycosylation during severe SARS-CoV-2 or Influenza A infection, revealing lower sialylation and higher galactosylation of IgA1 O-glycans in acute respiratory distress syndrome (ARDS), regardless of the underlying cause of the disease. Importantly, N-glycans displayed an infection-specific pattern, with N47 of IgA2 showing diminished sialylation and bisection, and N340/N327 of IgA1/2 demonstrating lower fucosylation and antennarity along with higher non-complex glycans in COVID-19 compared to Influenza. Notably, COVID-19 IgA possessed strong ability to induce NET formation and its glycosylation patterns correlated with extracellular DNA levels in plasma of critically ill COVID-19 patients. Our data underscores the necessity of further research on the role of IgA glycosylation in the modulation of pathogen-specific immune responses in COVID-19 and other infectious diseases. [ABSTRACT FROM AUTHOR]

Introduction Glycans are crucial macromolecules for all living organisms (Varki 2017). They are not only necessary for energy storage, but they are also directly involved in the regulation of numerous [...], Nearly all extracellular proteins undergo post-translational modification with sugar chains during their transit through the endoplasmic reticulum and the Golgi apparatus. These "sweet" modifications not only influence the activity of its carrier protein, but they themselves often have bioactivity, independent of the carrier function. Lactoferrin belongs to the group of glycoproteins and is modified with several different N-glycans. This minireview summarizes several studies dealing with the diverse glycosylation patterns of lactoferrin from different origins, and the potential impact of these post-translational modifications on the functionality of lactoferrin. A special emphasis is placed on the differences between human and bovine lactoferrin, because the latter form is often selected for the development of novel therapeutic approaches in humans. For this reason, the potential impact of the bovine-specific glycosylation patterns on the observed heterogeneous effects of lactoferrin in humans is discussed within this minireview. Key words: lactoferrin, N-glycans, high-mannose receptor, glycoproteins. Resume: Presque toutes les proteines extracellulaires subissent une modification post-traductionnelle qui consiste en l&apos;ajout de chaines de glucides durant leur transit a travers le reticulum endoplasmique et l&apos;appareil de Golgi. Ces modifications << sucrees >> influencent non seulement l&apos;activite de leur proteine porteuse, elles ont elles-memes une bioactivite independante de la fonction de transporteur. La lactoferrine appartient au groupe des glycoproteines et elle est modifiee par plusieurs N-glycanes differents. Cet article de minisynthese resume plusieurs etudes portant sur les differents patrons de glycosylation de la lactoferrine de differentes origines et sur l&apos;impact potentiel de ces modifications post-traductionnelles sur la fonctionnalite de la lactoferrine. Un accent particulier est place sur les differences qui existent entre la lactoferrine humaine et la lactoferrine bovine, puisque cette derniere est souvent choisie dans le developpement de nouvelles approches therapeutiques chez l&apos;humain. Pour cette raison, l&apos;impact potentiel des patrons de glycosylation specifiques au bovin sur les effets heterogenes observes de la lactoferrine chez l&apos;humain est discute dans cette minisynthese. [Traduit par la Redaction] Mots-cles : lactoferrine, N-glycanes, recepteur du mannose, glycoproteines.

N-glycosylation influences the effectiveness of immune globulin G (IgG) and thus the immunological downstream responses of immune cells. This impact arises from the presence of N-glycans within the Fc region, which not only alters the conformation of IgG but also influences its steric hindrance. Consequently, these modifications affect the interaction between IgG and its binding partners within the immune system. Moreover, this posttranslational modification vary according to the physiological condition of each individual. In this study, we examined the N-glycosylation of IgG in pigs from birth to five months of age. Our analysis identified a total of 48 distinct N-glycan structures. Remarkably, we observed defined changes in the composition of these N-glycans during postnatal development. The presence of agalactosylated and sialylated structures increases in relation to the number of N-glycans terminated by galactose residues during the first months of life. This shift may indicate a transition from passively transferred antibodies from the colostrum of the sow to the active production of endogenous IgG by the pig's own immune system. [ABSTRACT FROM AUTHOR]

Simple Summary: In addition to their function as energy sources, monosaccharides are used to build complex structured oligo- and polysaccharides, which play numerous essential roles as functional biomolecules. Such bioactive sugars are also key components of milk, since they have positive impacts on intestinal development, the gut microbiome, and an effective immune system, along with the learning and memory ability of offspring. Moreover, milk oligo- and polysaccharides have anti-adhesive properties against pathogenic microorganisms and viruses and are, therefore, important for the health of the mammary gland and the offspring. One key monosaccharide of such oligo- and polysaccharides is the sialic acid N-acetylneuraminic acid (Neu5Ac). Since bovine milk is not only important for calf health but also, in the case of colostrum, as a functional food for humans, it is of particular interest, at which time of lactation the highest amounts of these bioactive molecules are found in bovine milk. Our results demonstrate that on the day of calving, the highest amounts of Neu5Ac and its polymers are present in bovine milk and, thus, the sialic acid-dependent benefits of bovine milk are also highest at this time. Sialylated milk oligosaccharides and glycoconjugates have several positive effects on the mucosal barrier, the gut microbiome, and an effective immune system. For this reason, they are important biomolecules for mammary gland health and optimal development of offspring. In milk, the major sialic acid, N-acetylneuraminic acid (Neu5Ac), can be attached as monosialyl-residues or as polymers. To investigate the sialylation processes during lactation of German Holstein cows, we analyzed udder tissue in addition to milk at different time points of lactation. The analysis of the milk samples revealed that both the levels of Neu5Ac and its polymer, polysialic acid (polySia), rapidly decreased during the first three days of lactation, and a high interindividual variance was observed. In mature milk, however, the sialylation status remains relatively constant. The results indicate that mammary gland epithelial cells are one source for milk polySia, since immunohistochemistry of udder tissue exhibited strong polySia staining in these cells. Furthermore, both polysialyltransferases, ST8SiaII and ST8SiaIV, are expressed. Based on known functions of monosialyl residues and polySia, we discuss the potential impact of these biomolecules and the consequences of the heterogeneous sialylation status of milk in relation to udder health and offspring health. [ABSTRACT FROM AUTHOR]

Neutrophil extracellular traps ( NET) are formed against pathogens. However, various diseases are directly linked to this meshwork of DNA. The cytotoxic properties of extracellular histones especially seem to be an important trigger during these diseases. Furthermore, NET accumulation on implants is discussed to result in an impaired efficiency or failure, depending on the category of implant. Interestingly, mucins have been investigated as surface coatings potentially capable of reducing neutrophil adhesion. Similarly, polysialic acid was shown to inactivate the cytotoxic properties of extracellular histones. We wanted to combine the probability to decrease the adhesion of neutrophils using mucins with the capability of sialic acid polymers to counteract histone-mediated cytotoxicity. To this end, we elongate cervical mucins using bacterial polysialyltransferases. Subsequent cell-based experiments demonstrated the activity of elongated mucins against histone-mediated cytotoxicity. Thus, polysialylated mucins may represent a novel component to coat implants or to combat diseases with exaggerated NET formation. [ABSTRACT FROM AUTHOR]

Simple Summary: Bovine milk contains a high concentration of the protein lactoferrin. It is an important antimicrobial biomolecule, which is also present in other bodily fluids like blood and semen. However, not only the intact protein but also its cleavage products have antimicrobial activity. Perhaps, the best-known cleavage product of lactoferrin is the peptide lactoferricin that has significant antimicrobial capacity against a broad range of pathogens such as enterohemorrhagic Escherichia coli (EHEC). Interestingly, lactoferricin can interact with the sugar polymer polysialic acid, which is also present in milk, blood, and semen. In the present study, we tested if the binding to polysialic acid influences the biological activity of bovine lactoferricin. Remarkably, neither different amounts of polysialic acid nor different chain lengths of this sugar polymer influenced the antimicrobial activity of lactoferricin. The ability of polysialic acid to bind and not inactivate lactoferricin may allow the development of novel endogenous and biodegradable polysialylated surfaces and/or hydrogels, which can be loaded with the antimicrobial peptide lactoferricin for biomedical applications in veterinary and human medicine. The lactoferrin-derived peptide lactoferricin (LFcin) belongs to the family of antimicrobial peptides, and its bovine form has already been successfully applied to counteract enterohemorrhagic Escherichia coli (EHEC) infection. Recently, it was described that LFcin interacts with the sugar polymer polysialic acid (polySia) and that the binding of lactoferrin to polySia is mediated by LFcin, included in the N-terminal domain of lactoferrin. For this reason, the impact of polySia on the antimicrobial activity of bovine LFcin was investigated. Initially, the interaction of LFcin was characterized in more detail by native agarose gel electrophoresis, demonstrating that a chain length of 10 sialic acid residues was necessary to bind LFcin, whereas approximately twice-as-long chains were needed to detect binding of lactoferrin. Remarkably, the binding of polySia showed, independently of the chain length, no impact on the antimicrobial effects of LFcin. Thus, LFcin binds polySia without loss of its protective activity as an antimicrobial peptide. [ABSTRACT FROM AUTHOR]