Mucin Biopolymers As Broad-Spectrum Antiviral Agents

Lieleg, Oliver; Lieleg, Corinna; Bloom, Jesse D.; Buck, Christopher B.; Ribbeck, Katharina

doi:10.1021/bm3001292

Cited by 152 publications

(165 citation statements)

References 45 publications

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“…A previous study suggested that during IAV infection, mucin acts as an immobilization substrate for the virus on the cell surface (29). Furthermore, a recent study revealed that increased MUC5AC secretion appears to play a protective role against influenza virus infection (12).…”

Section: Galnt3 Expression Is Associated With Mucin Production and Thmentioning

confidence: 99%

Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

Nakamura

Horie

Daidoji

et al. 2016

J Virol

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Influenza A virus (IAV) affects the upper and lower respiratory tracts and rapidly induces the expression of mucins, which are common O-glycosylated proteins, on the epithelial surfaces of the respiratory tract. Although mucin production is associated with the inhibition of virus transmission as well as characteristic clinical symptoms, little is known regarding how mucins are produced on the surfaces of respiratory epithelial cells and how they affect IAV replication. In this study, we found that two microRNAs (miRNAs), miR-17-3p and miR-221, which target GalNAc transferase 3 (GALNT3) mRNA, are rapidly downregulated in human alveolar basal epithelial cells during the early stage of IAV infection. We demonstrated that the expression of GALNT3 mRNA is upregulated in an IAV replication-dependent fashion and leads to mucin production in bronchial epithelial cells. A lectin microarray analysis revealed that the stable expression of GALNT3 by human alveolar basal epithelial cells induces mucin-type O-glycosylation modifications similar to those present in IAV-infected cells, suggesting that GALNT3 promotes mucin-type O-linked glycosylation in IAV-infected cells. Notably, analyses using short interfering RNAs and miRNA mimics showed that GALNT3 knockdown significantly reduces IAV replication. Furthermore, IAV replication was markedly decreased in embryonic fibroblast cells obtained from galnt3-knockout mice. Interestingly, IAV-infected galnt3-knockout mice exhibited high mortality and severe pathological alterations in the lungs compared to those of wild-type mice. Our results demonstrate not only the molecular mechanism underlying rapid mucin production during IAV infection but also the contribution of O-linked glycosylation to the replication and propagation of IAV in lung cells. IMPORTANCEViral infections that affect the upper or lower respiratory tracts, such as IAV, rapidly induce mucin production on the epithelial surfaces of respiratory cells. However, the details of how mucin-type O-linked glycosylation is initiated by IAV infection and how mucin production affects viral replication have not yet been elucidated. In this study, we show that levels of two miRNAs that target the UDP-GalNAc transferase GALNT3 are markedly decreased during the early stage of IAV infection, resulting in the upregulation of GALNT3 mRNA. We also demonstrate that the expression of GALNT3 initiates mucin production and affects IAV replication in infected cells. This is the first report demonstrating the mechanism underlying the miRNA-mediated initiation of mucin-type O-glycosylation in IAV-infected cells and its role in viral replication. Our results have broad implications for understanding IAV replication and suggest a strategy for the development of novel anti-influenza approaches.

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Section: Galnt3 Expression Is Associated With Mucin Production and Thmentioning

confidence: 99%

Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

Nakamura

Horie

Daidoji

et al. 2016

J Virol

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“…NHBE cells produce mucus, which is a primary defense against respiratory pathogens and can inhibit influenza virus infection (48)(49)(50). Viral NA proteins are required for mucus degradation, allowing viral attachment to sialylated cellular receptors (50,51).…”

Section: Generation and Genetic Stability Of Recombinant Influenza Bmentioning

confidence: 99%

Fitness Costs for Influenza B Viruses Carrying Neuraminidase Inhibitor-Resistant Substitutions: Underscoring the Importance of E119A and H274Y

Burnham

Baranovich

Marathe

et al. 2014

Antimicrob Agents Chemother

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Influenza B viruses cause annual outbreaks of respiratory illness in humans and are increasingly recognized as a major cause of influenza-associated pediatric mortality. Neuraminidase (NA) inhibitors (NAIs) are the only available therapy for patients infected with influenza B viruses, and the potential emergence of NAI-resistant viruses is a public health concern. The NA substitutions located within the enzyme active site could not only reduce NAI susceptibility of influenza B virus but also affect virus fitness. In this study, we investigated the effect of single NA substitutions on the fitness of influenza B/Yamanashi/166/1998 viruses (Yamagata lineage). We generated recombinant viruses containing either wild-type (WT) NA or NA with a substitution in the catalytic (R371K) or framework (E119A, D198E, D198Y, I222T, H274Y, and N294S) residues. We assessed NAI susceptibility, NA biochemical properties, NA protein expression, and virus replication in vitro and in differentiated normal human bronchial epithelial (NHBE) cells. Our results showed that four NA substitutions (D198E, I222T, H274Y, and N294S) conferred reduced inhibition by oseltamivir and three (E119A, D198Y, and R371K) conferred highly reduced inhibition by oseltamivir, zanamivir, and peramivir. All NA substitutions, except for D198Y and R371K, were genetically stable after seven passages in MDCK cells. Cell surface NA protein expression was significantly increased by H274Y and N294S substitutions. Viruses with the E119A, I222T, H274Y, or N294S substitution were not attenuated in replication efficiency in vitro or in NHBE cells. Overall, viruses with the E119A or H274Y NA substitution possess fitness comparable to NAI-susceptible virus, and the acquisition of these substitutions by influenza B viruses should be closely monitored.

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“…Those mucins can act as an infection shield by trapping various viruses in the biopolymer matrix [ 1 ] and they reduce bacterial adhesion to surfaces. [ 2,3 ] Mucins also form highly hydrated and lubricative layers that protect the underlying epithelium from dehydration and shear stress that emerge during eye blinking or when swallowing food.…”

mentioning

confidence: 99%

Modulating Mucin Hydration and Lubrication by Deglycosylation and Polyethylene Glycol Binding

Crouzier

Boettcher

Geonnotti

et al. 2015

Adv Materials Inter

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glycoproteins, a family of high molecular weight and densely glycosylated biopolymers. Those mucins can act as an infection shield by trapping various viruses in the biopolymer matrix [ 1 ] and they reduce bacterial adhesion to surfaces. [ 2,3 ] Mucins also form highly hydrated and lubricative layers that protect the underlying epithelium from dehydration and shear stress that emerge during eye blinking or when swallowing food. Water typically accounts for up to 95% of the total mass in the mucus gel. [ 4,5 ] Shifts in the mucus water content correlate with substantial changes of the mucus barrier function [6][7][8] and result in important pathological disorders such as dry mouth [ 9 ] and dry eye. [ 10 ] Mucin-associated glycans contribute up to 80% of the molecular weight of mucins [ 11 ] and contain highly hydrated hydroxyl groups. Differences in the amount and composition of glycans from mucins extracted from pig stomachs and mucins from bovine submaxillary glands correlate with their capacity to adsorb water. [ 12 ] However, other properties such as protein composition also differ between these two mucin species, precluding the establishment of a defi nitive link between the presence of mucin glycans and hydration.Mucins, and other well-hydrated molecules such as zwitterionic polymers, polysaccharides, and polyelectrolytes are generally good boundary lubricants when adsorbed [ 13,14 ] or assembled in brush structures [15][16][17][18] on surfaces. Hence, mucin-associated glycans could also be essential for the lubricative function of mucus. In a related system, the mucin-like macromolecule lubricin showed a signifi cant decrease in lubricity when its associated glycans were removed. [ 19 ] Moreover, the lubricity of salivary fi lms, which contain mucins, has also been correlated with the total amount of glycosylation present in the fi lm. However, also here, the complexity of saliva composition precluded the identifi cation of the specifi c role of mucin glycosylation. [ 20 ] Hence, there is a need for a more defi ned experimental system to determine if mucin glycosylation is essential to the hydration and lubrication properties of mucins.This study explores the role of glycosylation in mucin hydration and lubricity, using mucin coatings as a simplifi ed model system. Such mucin coatings can reconstitute levels of surface hydration [ 21,22 ] and lubrication [23][24][25] similar to those found in native mucus. Our data show that the removal of mucin-bound glycans results in a signifi cant reduction in hydration and lubricity of the mucin-coated surface. We show that the hydration and lubricity of deglycosylated mucins can be partially A key property of mucin glycoproteins is their exceptional capacity to hydrate and lubricate surfaces. In vivo, mucins assemble into mucus hydrogels that cover the epithelium and protect it from dehydration and shear stress. A better understanding of the origin of these properties could lead to new treatment strategies for patients with poor mucus coverage, defective mucus produ...

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Mucin Biopolymers As Broad-Spectrum Antiviral Agents

Cited by 152 publications

References 45 publications

Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

Fitness Costs for Influenza B Viruses Carrying Neuraminidase Inhibitor-Resistant Substitutions: Underscoring the Importance of E119A and H274Y

Modulating Mucin Hydration and Lubrication by Deglycosylation and Polyethylene Glycol Binding

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