糖基化细胞外粘蛋白结构域可保护呼吸表面免受严重急性呼吸系统综合征冠状病毒2型感染。

IF 6.7 1区 医学 Q1 Immunology and Microbiology
PLoS Pathogens Pub Date : 2023-08-10 eCollection Date: 2023-08-01 DOI:10.1371/journal.ppat.1011571
Maitrayee Chatterjee, Liane Z X Huang, Anna Z Mykytyn, Chunyan Wang, Mart M Lamers, Bart Westendorp, Richard W Wubbolts, Jos P M van Putten, Berend-Jan Bosch, Bart L Haagmans, Karin Strijbis
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引用次数: 1

摘要

粘蛋白在保护呼吸道免受微生物感染方面发挥着重要作用,同时也是细菌和病毒粘附素的结合位点。高度O-糖基化的凝胶形成粘蛋白MUC5AC和MUC5B通过粘液纤毛清除来消除病原体。跨膜粘蛋白MUC1、MUC4和MUC16可以限制上皮顶端表面的微生物入侵。在这项研究中,我们确定了宿主粘蛋白和粘蛋白聚糖对严重急性呼吸系统综合征冠状病毒2型上皮进入的影响。人肺上皮Calu-3细胞在其细胞表面表达严重急性呼吸系统综合征冠状病毒2进入受体ACE2和高水平的糖基化MUC1,但不表达MUC4和MUC16。O-聚糖特异性粘蛋白酶StcE特异性地去除了MUC1细胞外结构域的糖基化部分,同时保留了下面的SEA结构域和细胞质尾部。Calu-3细胞的StcE处理显著增强了对严重急性呼吸系统综合征冠状病毒2型假病毒和真病毒的感染,而从上皮表面去除末端粘蛋白聚糖唾液酸和岩藻糖不影响病毒进入。在Calu-3细胞中,跨膜粘蛋白MUC1和ACE2位于顶端表面附近,StcE处理导致纯化的刺突蛋白的结合增强。MUC1和MUC16都在人类器官衍生的气液界面(ALI)分化的气道培养物表面表达,StcE治疗导致粘蛋白去除和严重急性呼吸系统综合征冠状病毒2型复制水平增加。在这些培养物中,MUC1在无纤毛细胞中高度表达,而MUC16在杯状细胞中富集。总之,不同跨膜粘蛋白的糖基化胞外结构域可能通过限制严重急性呼吸系统综合征冠状病毒2型的结合和进入,在不同的呼吸细胞类型中具有相似的保护功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Glycosylated extracellular mucin domains protect against SARS-CoV-2 infection at the respiratory surface.

Glycosylated extracellular mucin domains protect against SARS-CoV-2 infection at the respiratory surface.

Glycosylated extracellular mucin domains protect against SARS-CoV-2 infection at the respiratory surface.

Glycosylated extracellular mucin domains protect against SARS-CoV-2 infection at the respiratory surface.

Mucins play an essential role in protecting the respiratory tract against microbial infections while also acting as binding sites for bacterial and viral adhesins. The heavily O-glycosylated gel-forming mucins MUC5AC and MUC5B eliminate pathogens by mucociliary clearance. Transmembrane mucins MUC1, MUC4, and MUC16 can restrict microbial invasion at the apical surface of the epithelium. In this study, we determined the impact of host mucins and mucin glycans on epithelial entry of SARS-CoV-2. Human lung epithelial Calu-3 cells express the SARS-CoV-2 entry receptor ACE2 and high levels of glycosylated MUC1, but not MUC4 and MUC16, on their cell surface. The O-glycan-specific mucinase StcE specifically removed the glycosylated part of the MUC1 extracellular domain while leaving the underlying SEA domain and cytoplasmic tail intact. StcE treatment of Calu-3 cells significantly enhanced infection with SARS-CoV-2 pseudovirus and authentic virus, while removal of terminal mucin glycans sialic acid and fucose from the epithelial surface did not impact viral entry. In Calu-3 cells, the transmembrane mucin MUC1 and ACE2 are located to the apical surface in close proximity and StcE treatment results in enhanced binding of purified spike protein. Both MUC1 and MUC16 are expressed on the surface of human organoid-derived air-liquid interface (ALI) differentiated airway cultures and StcE treatment led to mucin removal and increased levels of SARS-CoV-2 replication. In these cultures, MUC1 was highly expressed in non-ciliated cells while MUC16 was enriched in goblet cells. In conclusion, the glycosylated extracellular domains of different transmembrane mucins might have similar protective functions in different respiratory cell types by restricting SARS-CoV-2 binding and entry.

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来源期刊
PLoS Pathogens
PLoS Pathogens 生物-病毒学
CiteScore
11.40
自引率
3.00%
发文量
598
审稿时长
2 months
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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