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Principal Investigator: Joseph TY Lau
Organization: ROSWELL PARK CANCER INSTITUTE CORP
Fiscal Year: 2020
Award: $183,648
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <19S Gamma Globulin><2019 novel coronavirus><2019-nCoV><7S Gamma Globulin><ABH Blood Group><ABO blood group system><ABO blood groups><ABO(H) blood groups><Acute><Address><Algorithms><Antibodies><Antigenic Determinants><Antigens><Attention><Attenuated><Autoimmune><Autoimmune Process><Automobile Driving><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Blood><Blood Plasma><Blood Platelets><Blood Reticuloendothelial System><COVID-19><COVID19><Cancers><Cell Maturation><Cell Survival><Cell Viability><Cell surface><Cell-Extracellular Matrix><Chondroitin 4 Sulfate><Chondroitin Sulfate A><Chronic><Coronaviridae><Coronavirus><Data><Deterioration><Disease><Disease Progression><Disorder><Dysfunction><ECM><Enzyme Gene><Enzymes><Epitopes><Extracellular Matrix><Functional disorder><Funding><Future><Glycans><Granulopoiesis><H Blood Group><H Blood Group System><IgG><IgM><Immune><Immune response><Immunes><Immunity><Immunoglobulin G><Immunoglobulin M><Immunological response><Individual><Inflammation><Inflammatory><Intravenous><Life><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Malignant Neoplasms><Malignant Tumor><Marrow platelet><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Metabolic Glycosylation><Mice><Mice Mammals><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Modality><Murine><Mus><N-Acetylneuraminic Acids><NIAID><National Institute of Allergy and Infectious Disease><Outcome><Parents><Pathogenesis><Pathologic><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Physiopathology><Plasma><Plasma Serum><Plasmapheresis><Platelets><Polysaccharides><Production><Property><Publishing><Recombinants><Reporting><Research Resources><Resources><Reticuloendothelial System, Serum, Plasma><Risk><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Severe acute respiratory syndrome coronavirus 2><Severity of illness><Sialic Acids><Sialyltransferases><Structure><Symptoms><Syndrome><System><Testing><Therapeutic><Therapeutic Plasma Exchange><Therapeutic Plasmapheresis><Thrombocytes><Thrombosis><Time><Tn antigen><Transmission><Viral><Work><Wuhan coronavirus><airway epithelium inflammation><airway inflammation><base><blood group><corona virus><corona virus disease 2019><coronavirus disease 2019><cytokine><disease severity><driving><effective therapy><effective treatment><glycosylation><healthy volunteer><host response><immunogen><immunoresponse><inflammation marker><inflammatory marker><insight><macrophage><malignancy><mimetics><mortality><neoplasm/cancer><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel therapeutics><novel therapy><organ transplant rejection><pandemic><pandemic disease><pathophysiology><prognostic ability><prognostic power><prognostic utility><prognostic value><response><thrombotic disease><thrombotic disorder><transmission process><tumor><volunteer>