Antiviral Antibody Fc Dysfunction Is Linked to Increased IgG1 Fucosylation in Long COVID
- 1Rutgers University
Abstract
BackgroundPersistent SARS-CoV-2 antigen is a leading hypothesis for post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID. Impaired Fc-mediated antiviral antibody function could contribute to inefficient clearance of infected cells and viral antigen despite preserved antibody levels. Therefore, we tested whether PASC is associated with altered Fc{gamma} receptor-mediated antibody function and differences in IgG1 Fc fucosylation, a major regulator of Fc effector function.
MethodsSerum samples from RECOVER-Adult participants with prior SARS-CoV-2 infection (99 PASC, 139 non-PASC) were analyzed for anti-SARS-CoV-2 spike receptor-binding domain (RBD) IgG and subclasses, Fc{gamma}RIIIa- and Fc{gamma}RIIa-mediated reporter activity as surrogate measures of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), anti-RBD IgG1 Fc glycosylation, and circulating fucose-modifying enzymes.
ResultsDespite higher anti-RBD IgG and IgG1 abundance, PASC sera showed lower ADCC- and ADCP-associated Fc{gamma}R reporter activity, including after normalization for antibody abundance. Anti-RBD IgG1 showed greater fucosylation in PASC samples (30 PASC, 34 non-PASC). Serum FUCA2 was lower in PASC samples (24 PASC, 34 non-PASC), whereas FUCA1 and soluble CD16a levels did not differ between the two groups.
ConclusionPASC is associated with impaired antiviral IgG Fc function, increased IgG1 Fc fucosylation, and reduced circulating FUCA2, identifying a glycoimmune axis that may contribute to impaired Fc-dependent antigen clearance and represents a potentially targetable pathway in Long COVID.
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BibTeX
@misc{ukey2026antiviral,
title = {{Antiviral Antibody Fc Dysfunction Is Linked to Increased IgG1 Fucosylation in Long COVID}},
author = {R. Ukey and I. E. Michailidis and P. Greenberg and T. Andrews and S. Y. Jung and H. Zheng and W. Honnen and A. Pinter and L. C. Kleinman and N. Bruiners and m. l. gennaro},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.26364044},
url = {https://www.medrxiv.org/content/10.64898/2026.09.28.26364044v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Antiviral Antibody Fc Dysfunction Is Linked to Increased IgG1 Fucosylation in Long COVID
AU - R. Ukey
AU - I. E. Michailidis
AU - P. Greenberg
AU - T. Andrews
AU - S. Y. Jung
AU - H. Zheng
AU - W. Honnen
AU - A. Pinter
AU - L. C. Kleinman
AU - N. Bruiners
AU - m. l. gennaro
PY - 2026
DA - 2026/09/28
PB - medRxiv
DO - 10.64898/2026.09.28.26364044
UR - https://www.medrxiv.org/content/10.64898/2026.09.28.26364044v1
AB - BackgroundPersistent SARS-CoV-2 antigen is a leading hypothesis for post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID. Impaired Fc-mediated antiviral antibody function could contribute to inefficient clearance of infected cells and viral antigen despite preserved antibody levels. Therefore, we tested whether PASC is associated with altered Fc{gamma} receptor-mediated antibody function and differences in IgG1 Fc fucosylation, a major regulator of Fc effector function. MethodsSerum samples from RECOVER-Adult participants with prior SARS-CoV-2 infection (99 PASC, 139 non-PASC) were analyzed for anti-SARS-CoV-2 spike receptor-binding domain (RBD) IgG and subclasses, Fc{gamma}RIIIa- and Fc{gamma}RIIa-mediated reporter activity as surrogate measures of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), anti-RBD IgG1 Fc glycosylation, and circulating fucose-modifying enzymes. ResultsDespite higher anti-RBD IgG and IgG1 abundance, PASC sera showed lower ADCC- and ADCP-associated Fc{gamma}R reporter activity, including after normalization for antibody abundance. Anti-RBD IgG1 showed greater fucosylation in PASC samples (30 PASC, 34 non-PASC). Serum FUCA2 was lower in PASC samples (24 PASC, 34 non-PASC), whereas FUCA1 and soluble CD16a levels did not differ between the two groups. ConclusionPASC is associated with impaired antiviral IgG Fc function, increased IgG1 Fc fucosylation, and reduced circulating FUCA2, identifying a glycoimmune axis that may contribute to impaired Fc-dependent antigen clearance and represents a potentially targetable pathway in Long COVID.
ER -