(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.

Public Health Relevance

Glycosylation abnormalities and the presence of unique anti-glycan antibodies in COVID-19 patient plasma implicate an overlooked but important aspect in SARS-CoV-2 pathogenesis. This work will generate the first- time information on the contribution of glycans in COVID-19 disease progression, with future potential novel therapeutics and also with prognostic value.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI140736-02S1
Application #
10159705
Study Section
Program Officer
Singleton, Kentner L
Project Start
2020-06-25
Project End
2022-08-31
Budget Start
2020-06-25
Budget End
2020-08-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263