ST6Gal-1 Sialyltransferase in Inflammation

项目摘要（补充） COVID-19是一种大流行病，其高死亡率是由高传染性和猖獗传播造成的 冠状病毒SARS-CoV-2不可预测的和非常迅速的危及生命的恶化， 一些但不是所有病毒呈阳性的患者仍未得到解决，需要立即予以关注。血浆置换， 用于治疗急性器官移植排斥反应患者，改善COVID-19的严重症状 这表明COVID-19中存在类似的免疫相关功能障碍。新的研究表明， 聚糖和糖基化是COVID-19发病机制中核心但被忽视的因素。其中 研究：1）A型血患者的预后明显差于O型血患者; 2）SARS-CoV-2 显示独特的聚糖结构，TF和Tn抗原通常仅在癌症中表达; 3） 接合宿主唾液酸聚糖表位以促进病毒进入和扩散在相关的Corona中有充分的记载 病毒，但尚未报告的SARS-CoV-2。 我们的初步数据支持COVID-19发病机制中的糖基化轴。比较10个病毒阳性 10名健康志愿者的患者，我们显示患者血浆中有1）IgG和IgM， 突出的细胞表面聚糖结构，包括对TF和Tn抗原;和2）抗- ABO从主要IgG变为IgM（仅10名患者和10名志愿者的p<0.001）。补充意见， 正在进行的母公司NIAID资助的R 01的一部分，确定了一种血源性聚糖修饰酶ST 6 GAL 1， 在促进IG产生、B细胞成熟、促进过渡期B细胞存活中的多效性功能 选择，同时通过抑制气道巨噬细胞释放细胞因子来减轻炎症。我们还 报道，血小板作为ST 6 GAL 1功能的关键贡献者，自然循环中的ST 6 GAL 1水平波动 而重组ST 6 GAL 1的接种减轻了急性气道炎症 对小鼠 我们建议使用更多的患者和健康供体血浆来扩大独特的抗- 聚糖抗体，并与疾病状态相关。我们还将讨论糖基化异常如何驱动 通过评估患者抗聚糖抗体激活血小板的能力，评估COVID 19中的血小板功能障碍。 这些目标应能对COVID-19中的血液聚糖产生明确的见解。未来的发展方向将考验该实用程序 聚糖、聚糖模拟物和/或重组聚糖修饰酶如ST 6 GAL 1作为治疗剂 COVID-19的模式。

Project Summary (Supplement) COVID-19 is a pandemic in which the high mortality rate is driven by high infectivity and rampant transmission of the causative corona virus, SARS-CoV-2. The unpredictable and very rapid life-threatening deterioration in some but not all viral-positive patients remains unsolved and requires immediate attention. Plasmapheresis, used to treat patients with acute organ transplant rejection, ameliorates the severe symptoms of COVID-19 patients, suggesting a similar immune-related dysfunction in COVID-19. Emerging studies implicate altered glycans and glycosylation as central but overlooked contributors in COVID-19 pathogenesis. Among these studies: 1) Blood group A patients have significantly worse outcomes than blood group O; 2) the SARS-CoV-2 displays unique glycan structures, the TF and Tn antigens that are normally only expressed in cancer; 3) engaging host sialic acid glyan epitopes to facilitate viral entry and dispersal is well document in related corona viruses although not yet reported for SARS-CoV-2. Our preliminary data supports a glycosylation-axis in COVID-19 pathogenesis. Comparing 10 viral-positive patients with 10 healthy volunteers, we showed patient plasma have 1) IgGs and IgMs directed again a number of prominent cell surface glycan structures, including against TF and Tn antigens; and 2) a striking shift of anti- ABO from predominantly IgG to IgM (p<0.001 with just 10 patients and 10 volunteers). Additional observations, part of the ongoing parent NIAID-funded R01, identified a blood-borne glycan-modifying enzyme, ST6GAL1 with pleiotropic functions in promoting Ig production, B cell maturation, facilitating transitional B cell survival during selection, while attenuating inflammation by muting cytokine release from airway macrophages. We have also reported that platelets as critical contributors to ST6GAL1 function, natural circulating ST6GAL1 levels fluctuate depending on disease status, and that inoculation of recombinant ST6GAL1 mitigated acute airway inflammation in mice. We propose using an increase number of patient and healthy donor plasma to expand upon the unique anti- glycan antibodies and correlate with disease status. We will also address how glycosylation abnormalities drive plate dysfunction in COVID19 by assessing the ability of patient anti-glycan antibodies to activate platelets. These Aims should yield definitive insights into blood glycans in COVID-19. Future directions will test the utility of glycans, glycan-mimetics, and/or recombinant glycan-modifying enzymes such as ST6GAL1 as therapeutic modalities for COVID-19.