Immunity system complexity: keeping fungus at bay (Introduction)

by David Turell , Wednesday, September 21, 2022, 17:52 (575 days ago) @ David Turell

With mucin:

https://www.nature.com/articles/s41589-022-01035-1.epdf?sharing_token=adqLkds10Ltif-DKi...

"Mucins are large gel-forming polymers inside the mucus barrier that inhibit the yeast-to-hyphal transition of Candida albicans, a key virulence trait of this important human fungal pathogen. However, the molecular motifs in mucins that inhibit filamentation remain unclear despite their potential for therapeutic interventions. Here, we determined that mucins display an abundance of virulence-attenuating molecules in the form of mucin O-glycans. We isolated and cataloged >100 mucin O-glycans from three major mucosal surfaces and established that they suppress filamentation and related phenotypes relevant to infection, including surface adhesion, biofilm formation and cross-kingdom competition between C. albicans and the bacterium Pseudomonas aeruginosa. Using synthetic O-glycans, we identified three structures (core 1, core 1 + fucose and core 2 + galactose) that are sufficient to inhibit filamentation with potency comparable to the complex O-glycan pool. Overall, this work identifies mucin O-glycans as host molecules with untapped therapeutic potential to manage fungal pathogens.

"Discussion:

"Research on mucus has traditionally focused on the role of mucins as scaffolding polymers. Here, we show that mucin O-glycans potently inhibit a range of virulence behaviors, which could be leveraged for therapeutic applications. Specifically, we show that mucin glycans across three major niches are potent regulators of C. albicans filamentation that block hyphal formation through Nrg1 and regulate community behavior.

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"Given the complexity and diversity of mucin glycans17,32 and dynamic glycosylation changes based on cell type38, developmental stage39 and disease state40, structural changes in host signals may activate or inhibit the function of specific O-glycans. Accordingly, we determined that core 1, core 1 + fucose and core 2 + galactose effectively suppress filamentation, while core 1 + sialic acid dampens this response. Hence, sialic acid, which is ubiquitously expressed on host cells41, may have an unappreciated role in modulating virulence. We posit that changes in glycosylation in disease states may mask or eliminate mucins’ protective functions. We conclude that the presentation of complex glycan structures in mucus contributes to a healthy mucosal environment, while degradation or modification of mucin glycans may trigger C. albicans to transition from commensal to pathogenic.

"The receptors involved in sensing mucin glycans, leading to NRG1 upregulation, remain unknown. Nrg1 regulation is temporally coordinated by two central signaling pathways mediating cell growth, leading to transient NRG1 downregulation and degradation of Nrg1 protein followed by occlusion of Nrg1 from hyphal-specific promoters that sustain hyphal development23. Mucin glycans may potentially function as ligands to mimic nutrient signaling pathways or may bind directly to C. albicans adhesins, thus modulating morphogenesis42. Uncovering the receptors involved in sensing mucin glycans and the pathways regulated by glycans will elucidate how C. albicans senses its host environment and how these cues regulate microbial antagonism, microbial community composition and pathogenesis."

Comment: shown to demonstrate the immune system has more weapons than B and T cells.