ST6Gal-1 Sialyltransferase in Inflammation

ST6Gal-1 唾液酸转移酶在炎症中的作用

• 批准号: 10159705
• 负责人: Joseph TY Lau
• 金额: $ 18.36万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159705
• 关键词: 2019-nCoV; ABO blood group system; Acute; Address; Algorithms; Antibodies; Antigens; Attention; Attenuated; Autoimmune Process; Automobile Driving; B-Lymphocytes; Blood; Blood Platelets; COVID-19; Cell Maturation; Cell Survival; Cell surface; Chondroitin Sulfate A; Chronic; Coronavirus; Data; Deterioration; Disease; Disease Progression; Enzymes; Epitopes; Extracellular Matrix; Functional disorder; Funding; Future; Granulopoiesis; Immune; Immune response; Immunity; Immunoglobulin G; Immunoglobulin M; Individual; Inflammation; Inflammatory; Intravenous; Life; Malignant Neoplasms; Mass Spectrum Analysis; Middle East Respiratory Syndrome Coronavirus; Modality; Mus; National Institute of Allergy and Infectious Disease; Outcome; Parents; Pathogenesis; Pathologic; Patient-Focused Outcomes; Patients; Plasma; Plasmapheresis; Polysaccharides; Production; Property; Publishing; Recombinants; Reporting; Resources; Risk; Severity of illness; Sialic Acids; Sialyltransferases; Structure; Symptoms; Syndrome; System; Testing; Therapeutic; Thrombosis; Time; Tn antigen; Viral; Work; airway inflammation; base; blood group; cytokine; effective therapy; glycosylation; healthy volunteer; inflammatory marker; insight; macrophage; mimetics; mortality; novel therapeutics; organ transplant rejection; pandemic disease; prognostic value; response; transmission process; tumor; volunteer

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.

项目摘要（补充）