Glycosylation-dependent opsonophagocytic activity of staphylococcal protein A antibodies
Abstract
Antibodies may bind to bacterial pathogens or their toxins to control infections, and their effector activity is mediated through the recruitment of complement component C1q or the engagement with Fcγ receptors (FcγRs). For bacterial pathogens that rely on a single toxin to cause disease, immunity correlates with toxin neutralization. Most other bacterial pathogens, includingStaphylococcus aureus, secrete numerous toxins and evolved multiple mechanisms to escape opsonization and complement killing. Several vaccine candidates targeting defined surface antigens ofS. aureushave failed to meet clinical endpoints. It is unclear that such failures can be solely attributed to the poor selection of antibody targets. Thus far, studies to delineate antibody-mediated uptake and killing of Gram-positive pathogens remain extremely limited. Here, we exploit 3F6-hIgG1, a human monoclonal antibody that binds and neutralizes the abundant surface-exposed Staphylococcal protein A (SpA). We find that galactosylation of 3F6-hIgG1 that favors C1q recruitment is indispensable for opsonophagocytic killing of staphylococci and for protection against bloodstream infection in animals. However, the simple removal of fucosyl residues, which results in reduced C1q binding and increased engagement with FcγR, maintains the opsonophagocytic killing and protective attributes of the antibody. We confirm these results by engineering 3F6-hIgG1 variants with biased binding toward C1q ormore »
- Authors:
-
[1];
[2];
[1]
- Argonne National Lab. (ANL), Argonne, IL (United States). Howard Taylor Ricketts Lab.; Univ. of Chicago, IL (United States). Dept. of Microbiology
- Univ. of Maryland, College Park, MD (United States). Dept. of Chemistry and Biochemistry
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1815835
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 117; Journal Issue: 37; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; monoclonal antibody; glycosylation; C1q; FcγR; Staphylococcal protein A
Citation Formats
Chen, Xinhai, Shi, Miaomiao, Tong, Xin, Kim, Hwan Keun, Wang, Lai-Xi, Schneewind, Olaf, and Missiakas, Dominique. Glycosylation-dependent opsonophagocytic activity of staphylococcal protein A antibodies. United States: N. p., 2020.
Web. doi:10.1073/pnas.2003621117.
Chen, Xinhai, Shi, Miaomiao, Tong, Xin, Kim, Hwan Keun, Wang, Lai-Xi, Schneewind, Olaf, & Missiakas, Dominique. Glycosylation-dependent opsonophagocytic activity of staphylococcal protein A antibodies. United States. https://doi.org/10.1073/pnas.2003621117
Chen, Xinhai, Shi, Miaomiao, Tong, Xin, Kim, Hwan Keun, Wang, Lai-Xi, Schneewind, Olaf, and Missiakas, Dominique. Thu .
"Glycosylation-dependent opsonophagocytic activity of staphylococcal protein A antibodies". United States. https://doi.org/10.1073/pnas.2003621117. https://www.osti.gov/servlets/purl/1815835.
@article{osti_1815835,
title = {Glycosylation-dependent opsonophagocytic activity of staphylococcal protein A antibodies},
author = {Chen, Xinhai and Shi, Miaomiao and Tong, Xin and Kim, Hwan Keun and Wang, Lai-Xi and Schneewind, Olaf and Missiakas, Dominique},
abstractNote = {Antibodies may bind to bacterial pathogens or their toxins to control infections, and their effector activity is mediated through the recruitment of complement component C1q or the engagement with Fcγ receptors (FcγRs). For bacterial pathogens that rely on a single toxin to cause disease, immunity correlates with toxin neutralization. Most other bacterial pathogens, includingStaphylococcus aureus, secrete numerous toxins and evolved multiple mechanisms to escape opsonization and complement killing. Several vaccine candidates targeting defined surface antigens ofS. aureushave failed to meet clinical endpoints. It is unclear that such failures can be solely attributed to the poor selection of antibody targets. Thus far, studies to delineate antibody-mediated uptake and killing of Gram-positive pathogens remain extremely limited. Here, we exploit 3F6-hIgG1, a human monoclonal antibody that binds and neutralizes the abundant surface-exposed Staphylococcal protein A (SpA). We find that galactosylation of 3F6-hIgG1 that favors C1q recruitment is indispensable for opsonophagocytic killing of staphylococci and for protection against bloodstream infection in animals. However, the simple removal of fucosyl residues, which results in reduced C1q binding and increased engagement with FcγR, maintains the opsonophagocytic killing and protective attributes of the antibody. We confirm these results by engineering 3F6-hIgG1 variants with biased binding toward C1q or FcγRs. While the therapeutic benefit of monoclonal antibodies against infectious disease agents may be debatable, the functional characterization of such antibodies represents a powerful tool for the development of correlates of protection that may guide future vaccine trials.},
doi = {10.1073/pnas.2003621117},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 37,
volume = 117,
place = {United States},
year = {Thu Aug 27 00:00:00 EDT 2020},
month = {Thu Aug 27 00:00:00 EDT 2020}
}
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