Glycosylation-dependent opsonophagocytic activity of staphylococcal protein A antibodies.
Glycosylation-dependent opsonophagocytic activity of staphylococcal protein A antibodies.
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DOI：
10.1073/pnas.2003621117
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发表时间：
2020-09-15
影响因子：
11.1
通讯作者：
Missiakas D
中科院分区：
文献类型：
--
作者：
Chen X;Shi M;Tong X;Kim HK;Wang LX;Schneewind O;Missiakas D
All currently licensed antibodies against bacteria target exotoxins. For most pathogens, neutralization of toxin(s) is not sufficient to prevent bacterial replication. Antibodies against surface determinants represent better candidates to enhance opsonophagocytic killing, but the mechanisms of action of such antibodies have not been systematically studied. Staphylococcal protein A is a conserved surface protein of Staphylococcus aureus and a crucial virulence determinant that manipulates B-cell responses and blocks deposition of opsonin. Monoclonal antibodies directed against SpA represent potential therapeutic agents as well as a formidable tool to identify and optimize effector functions of antibodies that can promote bacterial clearance. 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, including Staphylococcus aureus, secrete numerous toxins and evolved multiple mechanisms to escape opsonization and complement killing. Several vaccine candidates targeting defined surface antigens of S. aureus have 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.
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影响因子：
5.3
作者：
Kaplon, Helene;Reichert, Janice M.
通讯作者：
Reichert, Janice M.
影响因子：
6.4
作者：
Falugi F;Kim HK;Missiakas DM;Schneewind O
通讯作者：
Schneewind O
DOI：
10.1111/j.1749-6632.1974.tb41496.x
发表时间：
1974-01-01
影响因子：
5.2
作者：
FORSGREN, A;NORDSTRO.K
通讯作者：
NORDSTRO.K
影响因子：
5.4
作者：
FORSGREN, A;SVEDJELUND, A;WIGZELL, H
通讯作者：
WIGZELL, H
影响因子：
11.8
作者：
Lessa, Fernanda C.;Mu, Yi;Fridkin, Scott K.
通讯作者：
Fridkin, Scott K.