ST6Gal-1 Sialyltransferase in Inflammation
- Funded by National Institutes of Health (NIH)
- Total publications:0 publications
Grant number: unknown
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Key facts
Disease
COVID-19Start & end year
20202022Known Financial Commitments (USD)
$183,648Funder
National Institutes of Health (NIH)Principal Investigator
PendingResearch Location
United States of AmericaLead Research Institution
ROSWELL PARK CANCER INSTITUTE CORPResearch Priority Alignment
N/A
Research Category
Pathogen: natural history, transmission and diagnostics
Research Subcategory
Pathogen morphology, shedding & natural history
Special Interest Tags
N/A
Study Type
Non-Clinical
Clinical Trial Details
N/A
Broad Policy Alignment
Pending
Age Group
Unspecified
Vulnerable Population
Unspecified
Occupations of Interest
Unspecified
Abstract
Project Summary (Supplement)COVID-19 is a pandemic in which the high mortality rate is driven by high infectivity and rampant transmissionof 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-19patients, 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 coronaviruses 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 numberof 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 withpleiotropic functions in promoting Ig production, B cell maturation, facilitating transitional B cell survival duringselection, while attenuating inflammation by muting cytokine release from airway macrophages. We have alsoreported that platelets as critical contributors to ST6GAL1 function, natural circulating ST6GAL1 levels fluctuatedepending 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.