ST6Gal-1 Sialyltransferase in Inflammation

项目摘要(增补件) 新冠肺炎是一种流行病，其高死亡率是由高传染性和猖獗的传播所推动的 致病冠状病毒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)病毒阳性患者仍未得到解决，需要立即关注。血浆置换， 用于治疗急性器官移植排斥反应患者，改善新冠肺炎的严重症状 这表明新冠肺炎也存在类似的免疫相关功能障碍。新出现的研究表明改变了 多糖和糖基化是新冠肺炎发病机制中的中心但被忽视的贡献因素。其中包括 研究：1)A型血患者的预后明显比O型血差；2)SARS-CoV-2 显示独特的糖链结构，即通常只在癌症中表达的Tf和Tn抗原；3) 利用宿主唾液酸聚糖表位促进病毒进入和传播在相关的冠状中得到了很好的证明 病毒，尽管还没有关于SARS-CoV-2的报道。 我们的初步数据支持新冠肺炎发病机制中的糖化轴。比较10个病毒阳性的人 患者与10名健康志愿者，我们显示患者的血浆有1)免疫球蛋白和免疫球蛋白再次定向的数量 显著的细胞表面糖链结构，包括针对Tf和Tn抗原；以及2)抗Tf和Tn抗原的显著转变 ABO从以免疫球蛋白为主到免疫球蛋白M(P&lt；0.001，只有10名患者和10名志愿者)。其他观察结果， 作为正在进行的亲本NIAID资助的R01的一部分，鉴定了一种血液传播的葡聚糖修饰酶ST6GAL1 多种功能促进免疫球蛋白生成，B细胞成熟，促进过渡性B细胞存活 选择，同时通过抑制呼吸道巨噬细胞释放细胞因子来减轻炎症。我们还有 报道称，血小板作为ST6GAL1功能的关键贡献者，自然循环中的ST6GAL1水平波动 根据疾病状况，接种重组ST6GAL1可减轻急性呼吸道炎症 在老鼠身上。 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- 糖链抗体与疾病状态相关。我们还将讨论糖基化异常是如何推动 通过评估患者抗糖蛋白抗体激活血小板的能力来评估COVID19患者的平板功能障碍。 这些目标应该会对新冠肺炎中的血液葡聚糖产生最终的见解。未来的方向将测试该实用程序 作为治疗性的多聚糖、多聚糖模拟物和/或重组多聚糖修饰酶，如ST6GAL1 新冠肺炎的模式。

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.